US20040234529A1 - Helicobacter pylori adhesin binding group antigen - Google Patents
Helicobacter pylori adhesin binding group antigen Download PDFInfo
- Publication number
- US20040234529A1 US20040234529A1 US10/761,201 US76120104A US2004234529A1 US 20040234529 A1 US20040234529 A1 US 20040234529A1 US 76120104 A US76120104 A US 76120104A US 2004234529 A1 US2004234529 A1 US 2004234529A1
- Authority
- US
- United States
- Prior art keywords
- asn
- adhesin
- gly
- protein
- helicobacter pylori
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 title claims abstract description 77
- 239000000427 antigen Substances 0.000 title claims abstract description 42
- 102000036639 antigens Human genes 0.000 title claims abstract description 42
- 108091007433 antigens Proteins 0.000 title claims abstract description 42
- 230000027455 binding Effects 0.000 title claims abstract description 36
- 241000590002 Helicobacter pylori Species 0.000 title claims abstract description 29
- 229940037467 helicobacter pylori Drugs 0.000 title claims abstract description 29
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 70
- 108060003951 Immunoglobulin Proteins 0.000 claims abstract description 53
- 102000018358 immunoglobulin Human genes 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 48
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 43
- 230000000694 effects Effects 0.000 claims abstract description 32
- 210000004369 blood Anatomy 0.000 claims abstract description 25
- 239000008280 blood Substances 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 13
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 5
- 230000001175 peptic effect Effects 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 33
- 241000894006 Bacteria Species 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 29
- 244000005700 microbiome Species 0.000 claims description 28
- 230000001580 bacterial effect Effects 0.000 claims description 21
- 210000004027 cell Anatomy 0.000 claims description 18
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 241000287828 Gallus gallus Species 0.000 claims description 10
- 230000003053 immunization Effects 0.000 claims description 10
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 9
- 235000021277 colostrum Nutrition 0.000 claims description 7
- 210000003022 colostrum Anatomy 0.000 claims description 7
- 235000013336 milk Nutrition 0.000 claims description 7
- 210000004080 milk Anatomy 0.000 claims description 7
- 239000008267 milk Substances 0.000 claims description 7
- 108010000912 Egg Proteins Proteins 0.000 claims description 6
- 102000002322 Egg Proteins Human genes 0.000 claims description 6
- 235000013345 egg yolk Nutrition 0.000 claims description 6
- 210000002969 egg yolk Anatomy 0.000 claims description 6
- 241000282412 Homo Species 0.000 claims description 5
- 229960005486 vaccine Drugs 0.000 claims description 5
- 108010077805 Bacterial Proteins Proteins 0.000 claims description 4
- 238000012360 testing method Methods 0.000 claims description 4
- 241000186660 Lactobacillus Species 0.000 claims description 3
- 230000029142 excretion Effects 0.000 claims description 2
- 210000005170 neoplastic cell Anatomy 0.000 claims description 2
- 206010019375 Helicobacter infections Diseases 0.000 claims 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims 6
- 229940127557 pharmaceutical product Drugs 0.000 claims 5
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- 241000191940 Staphylococcus Species 0.000 claims 1
- 210000000628 antibody-producing cell Anatomy 0.000 claims 1
- 239000012535 impurity Substances 0.000 claims 1
- 239000002773 nucleotide Substances 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 25
- 208000015181 infectious disease Diseases 0.000 abstract description 19
- 230000002265 prevention Effects 0.000 abstract description 14
- 238000002560 therapeutic procedure Methods 0.000 abstract description 13
- 108020004414 DNA Proteins 0.000 abstract description 12
- 108091028043 Nucleic acid sequence Proteins 0.000 abstract description 5
- 208000007882 Gastritis Diseases 0.000 abstract description 3
- 238000011321 prophylaxis Methods 0.000 abstract description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract description 2
- 241000589989 Helicobacter Species 0.000 abstract description 2
- 238000002255 vaccination Methods 0.000 abstract 2
- 235000018102 proteins Nutrition 0.000 description 34
- 102000005962 receptors Human genes 0.000 description 25
- 108020003175 receptors Proteins 0.000 description 25
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 24
- 239000012528 membrane Substances 0.000 description 24
- 238000002649 immunization Methods 0.000 description 21
- 210000004379 membrane Anatomy 0.000 description 21
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 19
- 239000002953 phosphate buffered saline Substances 0.000 description 19
- 241000283690 Bos taurus Species 0.000 description 18
- 229940072221 immunoglobulins Drugs 0.000 description 15
- 229960002685 biotin Drugs 0.000 description 12
- 235000020958 biotin Nutrition 0.000 description 12
- 239000011616 biotin Substances 0.000 description 12
- 229920001213 Polysorbate 20 Polymers 0.000 description 10
- 239000002671 adjuvant Substances 0.000 description 10
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 241000124008 Mammalia Species 0.000 description 8
- 239000012722 SDS sample buffer Substances 0.000 description 8
- 108010090804 Streptavidin Proteins 0.000 description 8
- 150000001413 amino acids Chemical group 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- 108010044940 alanylglutamine Proteins 0.000 description 7
- 210000001035 gastrointestinal tract Anatomy 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000001262 western blot Methods 0.000 description 7
- 230000000890 antigenic effect Effects 0.000 description 6
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 239000003053 toxin Substances 0.000 description 6
- 231100000765 toxin Toxicity 0.000 description 6
- 108700012359 toxins Proteins 0.000 description 6
- 102000009027 Albumins Human genes 0.000 description 5
- 108010088751 Albumins Proteins 0.000 description 5
- NWOSHVVPKDQKKT-RYUDHWBXSA-N Gly-Tyr-Gln Chemical compound [H]NCC(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O NWOSHVVPKDQKKT-RYUDHWBXSA-N 0.000 description 5
- LPFBXFILACZHIB-LAEOZQHASA-N Ile-Gly-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)O)C(=O)O)N LPFBXFILACZHIB-LAEOZQHASA-N 0.000 description 5
- 101710116435 Outer membrane protein Proteins 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 210000004408 hybridoma Anatomy 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- CRWFEKLFPVRPBV-CIUDSAMLSA-N Ala-Gln-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(O)=O CRWFEKLFPVRPBV-CIUDSAMLSA-N 0.000 description 4
- 239000004971 Cross linker Substances 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- JPHYJQHPILOKHC-ACZMJKKPSA-N Glu-Asp-Asp Chemical compound OC(=O)CC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O JPHYJQHPILOKHC-ACZMJKKPSA-N 0.000 description 4
- QAMMIGULQSIRCD-IRXDYDNUSA-N Gly-Phe-Tyr Chemical compound C([C@H](NC(=O)C[NH3+])C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C([O-])=O)C1=CC=CC=C1 QAMMIGULQSIRCD-IRXDYDNUSA-N 0.000 description 4
- 241000880493 Leptailurus serval Species 0.000 description 4
- 239000002033 PVDF binder Substances 0.000 description 4
- IEZVHOULSUULHD-XGEHTFHBSA-N Thr-Ser-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(O)=O IEZVHOULSUULHD-XGEHTFHBSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 108010047857 aspartylglycine Proteins 0.000 description 4
- 230000029586 bacterial cell surface binding Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 230000001900 immune effect Effects 0.000 description 4
- 229940099472 immunoglobulin a Drugs 0.000 description 4
- 239000003022 immunostimulating agent Substances 0.000 description 4
- 230000005291 magnetic effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- SZNGQSBRHFMZLT-IHRRRGAJSA-N Asn-Pro-Phe Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O SZNGQSBRHFMZLT-IHRRRGAJSA-N 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- 102000009016 Cholera Toxin Human genes 0.000 description 3
- 108010049048 Cholera Toxin Proteins 0.000 description 3
- ATVYZJGOZLVXDK-IUCAKERBSA-N Glu-Leu-Gly Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O ATVYZJGOZLVXDK-IUCAKERBSA-N 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- JBCLFWXMTIKCCB-UHFFFAOYSA-N H-Gly-Phe-OH Natural products NCC(=O)NC(C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-UHFFFAOYSA-N 0.000 description 3
- IZPVWNSAVUQBGP-CIUDSAMLSA-N Leu-Ser-Asp Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O IZPVWNSAVUQBGP-CIUDSAMLSA-N 0.000 description 3
- 102000017033 Porins Human genes 0.000 description 3
- 108010013381 Porins Proteins 0.000 description 3
- 108020004511 Recombinant DNA Proteins 0.000 description 3
- CRJZZXMAADSBBQ-SRVKXCTJSA-N Ser-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CO CRJZZXMAADSBBQ-SRVKXCTJSA-N 0.000 description 3
- 102000007562 Serum Albumin Human genes 0.000 description 3
- 108010071390 Serum Albumin Proteins 0.000 description 3
- UXUFNBVCPAWACG-SIUGBPQLSA-N Tyr-Gln-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N UXUFNBVCPAWACG-SIUGBPQLSA-N 0.000 description 3
- PQSNETRGCRUOGP-KKHAAJSZSA-N Val-Thr-Asn Chemical compound CC(C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@H](C(O)=O)CC(N)=O PQSNETRGCRUOGP-KKHAAJSZSA-N 0.000 description 3
- OXNGKCPRVRBHPO-XLMUYGLTSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-beta-D-GlcpNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](CO)O[C@@H](O)[C@@H]2NC(C)=O)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O OXNGKCPRVRBHPO-XLMUYGLTSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 230000021615 conjugation Effects 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 3
- 238000001493 electron microscopy Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 3
- 210000001156 gastric mucosa Anatomy 0.000 description 3
- 108010078144 glutaminyl-glycine Proteins 0.000 description 3
- 108010087823 glycyltyrosine Proteins 0.000 description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 3
- 239000010931 gold Substances 0.000 description 3
- 229910052737 gold Inorganic materials 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000007918 pathogenicity Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003345 scintillation counting Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 108010061238 threonyl-glycine Proteins 0.000 description 3
- 239000000304 virulence factor Substances 0.000 description 3
- 230000007923 virulence factor Effects 0.000 description 3
- HHRAXZAYZFFRAM-CIUDSAMLSA-N Ala-Leu-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O HHRAXZAYZFFRAM-CIUDSAMLSA-N 0.000 description 2
- QHUOOCKNNURZSL-IHRRRGAJSA-N Arg-Tyr-Ser Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(O)=O QHUOOCKNNURZSL-IHRRRGAJSA-N 0.000 description 2
- PDQBXRSOSCTGKY-ACZMJKKPSA-N Asn-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N PDQBXRSOSCTGKY-ACZMJKKPSA-N 0.000 description 2
- ULRPXVNMIIYDDJ-ACZMJKKPSA-N Asn-Glu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N ULRPXVNMIIYDDJ-ACZMJKKPSA-N 0.000 description 2
- NPZJLGMWMDNQDD-GHCJXIJMSA-N Asn-Ser-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NPZJLGMWMDNQDD-GHCJXIJMSA-N 0.000 description 2
- MYTHOBCLNIOFBL-SRVKXCTJSA-N Asn-Ser-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O MYTHOBCLNIOFBL-SRVKXCTJSA-N 0.000 description 2
- LRCIOEVFVGXZKB-BZSNNMDCSA-N Asn-Tyr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O LRCIOEVFVGXZKB-BZSNNMDCSA-N 0.000 description 2
- 101710112752 Cytotoxin Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- XMPXVJIDADUOQB-RCOVLWMOSA-N Gly-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C([O-])=O)NC(=O)CNC(=O)C[NH3+] XMPXVJIDADUOQB-RCOVLWMOSA-N 0.000 description 2
- SWQALSGKVLYKDT-UHFFFAOYSA-N Gly-Ile-Ala Natural products NCC(=O)NC(C(C)CC)C(=O)NC(C)C(O)=O SWQALSGKVLYKDT-UHFFFAOYSA-N 0.000 description 2
- HKSNHPVETYYJBK-LAEOZQHASA-N Gly-Ile-Glu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)CN HKSNHPVETYYJBK-LAEOZQHASA-N 0.000 description 2
- WDEHMRNSGHVNOH-VHSXEESVSA-N Gly-Lys-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCCCN)NC(=O)CN)C(=O)O WDEHMRNSGHVNOH-VHSXEESVSA-N 0.000 description 2
- HZMLFETXHFHGBB-UGYAYLCHSA-N Ile-Asn-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N HZMLFETXHFHGBB-UGYAYLCHSA-N 0.000 description 2
- PJLLMGWWINYQPB-PEFMBERDSA-N Ile-Asn-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N PJLLMGWWINYQPB-PEFMBERDSA-N 0.000 description 2
- GECLQMBTZCPAFY-PEFMBERDSA-N Ile-Gln-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)O)N GECLQMBTZCPAFY-PEFMBERDSA-N 0.000 description 2
- LJKDGRWXYUTRSH-YVNDNENWSA-N Ile-Gln-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N LJKDGRWXYUTRSH-YVNDNENWSA-N 0.000 description 2
- WNGVUZWBXZKQES-YUMQZZPRSA-N Leu-Ala-Gly Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCC(O)=O WNGVUZWBXZKQES-YUMQZZPRSA-N 0.000 description 2
- DBVWMYGBVFCRBE-CIUDSAMLSA-N Leu-Asn-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O DBVWMYGBVFCRBE-CIUDSAMLSA-N 0.000 description 2
- RFUBXQQFJFGJFV-GUBZILKMSA-N Leu-Asn-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O RFUBXQQFJFGJFV-GUBZILKMSA-N 0.000 description 2
- VGPCJSXPPOQPBK-YUMQZZPRSA-N Leu-Gly-Ser Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O VGPCJSXPPOQPBK-YUMQZZPRSA-N 0.000 description 2
- VUBIPAHVHMZHCM-KKUMJFAQSA-N Leu-Tyr-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CO)C(O)=O)CC1=CC=C(O)C=C1 VUBIPAHVHMZHCM-KKUMJFAQSA-N 0.000 description 2
- WRODMZBHNNPRLN-SRVKXCTJSA-N Lys-Leu-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O WRODMZBHNNPRLN-SRVKXCTJSA-N 0.000 description 2
- YBAFDPFAUTYYRW-UHFFFAOYSA-N N-L-alpha-glutamyl-L-leucine Natural products CC(C)CC(C(O)=O)NC(=O)C(N)CCC(O)=O YBAFDPFAUTYYRW-UHFFFAOYSA-N 0.000 description 2
- KZNQNBZMBZJQJO-UHFFFAOYSA-N N-glycyl-L-proline Natural products NCC(=O)N1CCCC1C(O)=O KZNQNBZMBZJQJO-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101100342977 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) leu-1 gene Proteins 0.000 description 2
- NQZFFLBPNDLTPO-DLOVCJGASA-N Ser-Phe-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CO)N NQZFFLBPNDLTPO-DLOVCJGASA-N 0.000 description 2
- JZRYFUGREMECBH-XPUUQOCRSA-N Ser-Val-Gly Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O JZRYFUGREMECBH-XPUUQOCRSA-N 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 241000473945 Theria <moth genus> Species 0.000 description 2
- LMMDEZPNUTZJAY-GCJQMDKQSA-N Thr-Asp-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(O)=O LMMDEZPNUTZJAY-GCJQMDKQSA-N 0.000 description 2
- KGKWKSSSQGGYAU-SUSMZKCASA-N Thr-Gln-Thr Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KGKWKSSSQGGYAU-SUSMZKCASA-N 0.000 description 2
- PAXANSWUSVPFNK-IUKAMOBKSA-N Thr-Ile-Asn Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H]([C@@H](C)O)N PAXANSWUSVPFNK-IUKAMOBKSA-N 0.000 description 2
- YOOAQCZYZHGUAZ-KATARQTJSA-N Thr-Leu-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O YOOAQCZYZHGUAZ-KATARQTJSA-N 0.000 description 2
- JLNMFGCJODTXDH-WEDXCCLWSA-N Thr-Lys-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)NCC(O)=O JLNMFGCJODTXDH-WEDXCCLWSA-N 0.000 description 2
- GQPQJNMVELPZNQ-GBALPHGKSA-N Thr-Ser-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N)O GQPQJNMVELPZNQ-GBALPHGKSA-N 0.000 description 2
- COYHRQWNJDJCNA-NUJDXYNKSA-N Thr-Thr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O COYHRQWNJDJCNA-NUJDXYNKSA-N 0.000 description 2
- NOOMDULIORCDNF-IRXDYDNUSA-N Tyr-Gly-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O NOOMDULIORCDNF-IRXDYDNUSA-N 0.000 description 2
- 101800000970 Vacuolating cytotoxin Proteins 0.000 description 2
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 108010086434 alanyl-seryl-glycine Proteins 0.000 description 2
- 108010005233 alanylglutamic acid Proteins 0.000 description 2
- OXNGKCPRVRBHPO-VIXGDSECSA-N alpha-L-Fucp-(1->2)-beta-D-Galp-(1->3)-[alpha-L-Fucp-(1->4)]-D-GlcNAc Chemical compound O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@H]2[C@@H]([C@@H](CO)OC(O)[C@@H]2NC(C)=O)O[C@H]2[C@H]([C@H](O)[C@H](O)[C@H](C)O2)O)O[C@H](CO)[C@H](O)[C@@H]1O OXNGKCPRVRBHPO-VIXGDSECSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- -1 antibodies Proteins 0.000 description 2
- 108010062796 arginyllysine Proteins 0.000 description 2
- 108010077245 asparaginyl-proline Proteins 0.000 description 2
- 108010092854 aspartyllysine Proteins 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000000718 duodenal ulcer Diseases 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 108010066198 glycyl-leucyl-phenylalanine Proteins 0.000 description 2
- 108010077435 glycyl-phenylalanyl-glycine Proteins 0.000 description 2
- 108010089804 glycyl-threonine Proteins 0.000 description 2
- 108010050848 glycylleucine Proteins 0.000 description 2
- 108010015792 glycyllysine Proteins 0.000 description 2
- 108010077515 glycylproline Proteins 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 229940039696 lactobacillus Drugs 0.000 description 2
- 108010047926 leucyl-lysyl-tyrosine Proteins 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 108010064235 lysylglycine Proteins 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 210000003550 mucous cell Anatomy 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 108010084525 phenylalanyl-phenylalanyl-glycine Proteins 0.000 description 2
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 108010029020 prolylglycine Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 230000006920 protein precipitation Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 108010048397 seryl-lysyl-leucine Proteins 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 108010080629 tryptophan-leucine Proteins 0.000 description 2
- 108010003137 tyrosyltyrosine Proteins 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 229940125575 vaccine candidate Drugs 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 108010083651 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase Proteins 0.000 description 1
- 101710111881 Agglutinin-like protein 3 Proteins 0.000 description 1
- 101710111885 Agglutinin-like protein 4 Proteins 0.000 description 1
- HHGYNJRJIINWAK-FXQIFTODSA-N Ala-Ala-Arg Chemical compound C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N HHGYNJRJIINWAK-FXQIFTODSA-N 0.000 description 1
- BUANFPRKJKJSRR-ACZMJKKPSA-N Ala-Ala-Gln Chemical compound C[C@H]([NH3+])C(=O)N[C@@H](C)C(=O)N[C@H](C([O-])=O)CCC(N)=O BUANFPRKJKJSRR-ACZMJKKPSA-N 0.000 description 1
- TTXMOJWKNRJWQJ-FXQIFTODSA-N Ala-Arg-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)C)CCCN=C(N)N TTXMOJWKNRJWQJ-FXQIFTODSA-N 0.000 description 1
- WYPUMLRSQMKIJU-BPNCWPANSA-N Ala-Arg-Tyr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WYPUMLRSQMKIJU-BPNCWPANSA-N 0.000 description 1
- YAXNATKKPOWVCP-ZLUOBGJFSA-N Ala-Asn-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(O)=O YAXNATKKPOWVCP-ZLUOBGJFSA-N 0.000 description 1
- PXKLCFFSVLKOJM-ACZMJKKPSA-N Ala-Asn-Glu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O PXKLCFFSVLKOJM-ACZMJKKPSA-N 0.000 description 1
- CVGNCMIULZNYES-WHFBIAKZSA-N Ala-Asn-Gly Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O CVGNCMIULZNYES-WHFBIAKZSA-N 0.000 description 1
- YSMPVONNIWLJML-FXQIFTODSA-N Ala-Asp-Pro Chemical compound C[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N1CCC[C@H]1C(O)=O YSMPVONNIWLJML-FXQIFTODSA-N 0.000 description 1
- BTYTYHBSJKQBQA-GCJQMDKQSA-N Ala-Asp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](C)N)O BTYTYHBSJKQBQA-GCJQMDKQSA-N 0.000 description 1
- LGFCAXJBAZESCF-ACZMJKKPSA-N Ala-Gln-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O LGFCAXJBAZESCF-ACZMJKKPSA-N 0.000 description 1
- CSAHOYQKNHGDHX-ACZMJKKPSA-N Ala-Gln-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CSAHOYQKNHGDHX-ACZMJKKPSA-N 0.000 description 1
- OQCPATDFWYYDDX-HGNGGELXSA-N Ala-Gln-His Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O OQCPATDFWYYDDX-HGNGGELXSA-N 0.000 description 1
- NJPMYXWVWQWCSR-ACZMJKKPSA-N Ala-Glu-Asn Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NJPMYXWVWQWCSR-ACZMJKKPSA-N 0.000 description 1
- KXEVYGKATAMXJJ-ACZMJKKPSA-N Ala-Glu-Asp Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(O)=O KXEVYGKATAMXJJ-ACZMJKKPSA-N 0.000 description 1
- BGNLUHXLSAQYRQ-FXQIFTODSA-N Ala-Glu-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O BGNLUHXLSAQYRQ-FXQIFTODSA-N 0.000 description 1
- GGNHBHYDMUDXQB-KBIXCLLPSA-N Ala-Glu-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)N GGNHBHYDMUDXQB-KBIXCLLPSA-N 0.000 description 1
- HXNNRBHASOSVPG-GUBZILKMSA-N Ala-Glu-Leu Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O HXNNRBHASOSVPG-GUBZILKMSA-N 0.000 description 1
- LTSBJNNXPBBNDT-HGNGGELXSA-N Ala-His-Gln Chemical compound N[C@@H](C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CCC(N)=O)C(=O)O LTSBJNNXPBBNDT-HGNGGELXSA-N 0.000 description 1
- FAJIYNONGXEXAI-CQDKDKBSSA-N Ala-His-Phe Chemical compound C([C@H](NC(=O)[C@@H](N)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 FAJIYNONGXEXAI-CQDKDKBSSA-N 0.000 description 1
- IFKQPMZRDQZSHI-GHCJXIJMSA-N Ala-Ile-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O IFKQPMZRDQZSHI-GHCJXIJMSA-N 0.000 description 1
- GSHKMNKPMLXSQW-KBIXCLLPSA-N Ala-Ile-Gln Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C)N GSHKMNKPMLXSQW-KBIXCLLPSA-N 0.000 description 1
- AWZKCUCQJNTBAD-SRVKXCTJSA-N Ala-Leu-Lys Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN AWZKCUCQJNTBAD-SRVKXCTJSA-N 0.000 description 1
- SOBIAADAMRHGKH-CIUDSAMLSA-N Ala-Leu-Ser Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(O)=O SOBIAADAMRHGKH-CIUDSAMLSA-N 0.000 description 1
- MEFILNJXAVSUTO-JXUBOQSCSA-N Ala-Leu-Thr Chemical compound C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MEFILNJXAVSUTO-JXUBOQSCSA-N 0.000 description 1
- AJBVYEYZVYPFCF-CIUDSAMLSA-N Ala-Lys-Asn Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O AJBVYEYZVYPFCF-CIUDSAMLSA-N 0.000 description 1
- FUKFQILQFQKHLE-DCAQKATOSA-N Ala-Lys-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(O)=O FUKFQILQFQKHLE-DCAQKATOSA-N 0.000 description 1
- RAAWHFXHAACDFT-FXQIFTODSA-N Ala-Met-Asn Chemical compound CSCC[C@H](NC(=O)[C@H](C)N)C(=O)N[C@@H](CC(N)=O)C(O)=O RAAWHFXHAACDFT-FXQIFTODSA-N 0.000 description 1
- RUXQNKVQSKOOBS-JURCDPSOSA-N Ala-Phe-Ile Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O RUXQNKVQSKOOBS-JURCDPSOSA-N 0.000 description 1
- DCVYRWFAMZFSDA-ZLUOBGJFSA-N Ala-Ser-Ala Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O DCVYRWFAMZFSDA-ZLUOBGJFSA-N 0.000 description 1
- RMAWDDRDTRSZIR-ZLUOBGJFSA-N Ala-Ser-Asp Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O RMAWDDRDTRSZIR-ZLUOBGJFSA-N 0.000 description 1
- WQKAQKZRDIZYNV-VZFHVOOUSA-N Ala-Ser-Thr Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O WQKAQKZRDIZYNV-VZFHVOOUSA-N 0.000 description 1
- XQNRANMFRPCFFW-GCJQMDKQSA-N Ala-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C)N)O XQNRANMFRPCFFW-GCJQMDKQSA-N 0.000 description 1
- BHFOJPDOQPWJRN-XDTLVQLUSA-N Ala-Tyr-Gln Chemical compound C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CCC(N)=O)C(O)=O BHFOJPDOQPWJRN-XDTLVQLUSA-N 0.000 description 1
- YEBZNKPPOHFZJM-BPNCWPANSA-N Ala-Tyr-Val Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O YEBZNKPPOHFZJM-BPNCWPANSA-N 0.000 description 1
- VHAQSYHSDKERBS-XPUUQOCRSA-N Ala-Val-Gly Chemical compound C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)NCC(O)=O VHAQSYHSDKERBS-XPUUQOCRSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- IASNWHAGGYTEKX-IUCAKERBSA-N Arg-Arg-Gly Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(O)=O IASNWHAGGYTEKX-IUCAKERBSA-N 0.000 description 1
- PQWTZSNVWSOFFK-FXQIFTODSA-N Arg-Asp-Asn Chemical compound C(C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)CN=C(N)N PQWTZSNVWSOFFK-FXQIFTODSA-N 0.000 description 1
- PAPSMOYMQDWIOR-AVGNSLFASA-N Arg-Lys-Val Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O PAPSMOYMQDWIOR-AVGNSLFASA-N 0.000 description 1
- PYZPXCZNQSEHDT-GUBZILKMSA-N Arg-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCN=C(N)N)N PYZPXCZNQSEHDT-GUBZILKMSA-N 0.000 description 1
- CNBIWSCSSCAINS-UFYCRDLUSA-N Arg-Tyr-Tyr Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O CNBIWSCSSCAINS-UFYCRDLUSA-N 0.000 description 1
- SWLOHUMCUDRTCL-ZLUOBGJFSA-N Asn-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N SWLOHUMCUDRTCL-ZLUOBGJFSA-N 0.000 description 1
- SLKLLQWZQHXYSV-CIUDSAMLSA-N Asn-Ala-Lys Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(O)=O SLKLLQWZQHXYSV-CIUDSAMLSA-N 0.000 description 1
- DNYRZPOWBTYFAF-IHRRRGAJSA-N Asn-Arg-Tyr Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(=O)N)N)O DNYRZPOWBTYFAF-IHRRRGAJSA-N 0.000 description 1
- DAPLJWATMAXPPZ-CIUDSAMLSA-N Asn-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC(N)=O DAPLJWATMAXPPZ-CIUDSAMLSA-N 0.000 description 1
- APHUDFFMXFYRKP-CIUDSAMLSA-N Asn-Asn-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N APHUDFFMXFYRKP-CIUDSAMLSA-N 0.000 description 1
- NLCDVZJDEXIDDL-BIIVOSGPSA-N Asn-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(=O)N)N)C(=O)O NLCDVZJDEXIDDL-BIIVOSGPSA-N 0.000 description 1
- KXFCBAHYSLJCCY-ZLUOBGJFSA-N Asn-Asn-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O KXFCBAHYSLJCCY-ZLUOBGJFSA-N 0.000 description 1
- QHBMKQWOIYJYMI-BYULHYEWSA-N Asn-Asn-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O QHBMKQWOIYJYMI-BYULHYEWSA-N 0.000 description 1
- UPALZCBCKAMGIY-PEFMBERDSA-N Asn-Gln-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UPALZCBCKAMGIY-PEFMBERDSA-N 0.000 description 1
- OKZOABJQOMAYEC-NUMRIWBASA-N Asn-Gln-Thr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O OKZOABJQOMAYEC-NUMRIWBASA-N 0.000 description 1
- OGMDXNFGPOPZTK-GUBZILKMSA-N Asn-Glu-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)N)N OGMDXNFGPOPZTK-GUBZILKMSA-N 0.000 description 1
- MSBDSTRUMZFSEU-PEFMBERDSA-N Asn-Glu-Ile Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O MSBDSTRUMZFSEU-PEFMBERDSA-N 0.000 description 1
- CTQIOCMSIJATNX-WHFBIAKZSA-N Asn-Gly-Ala Chemical compound [H]N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(O)=O CTQIOCMSIJATNX-WHFBIAKZSA-N 0.000 description 1
- RAQMSGVCGSJKCL-FOHZUACHSA-N Asn-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(N)=O RAQMSGVCGSJKCL-FOHZUACHSA-N 0.000 description 1
- PNHQRQTVBRDIEF-CIUDSAMLSA-N Asn-Leu-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)N PNHQRQTVBRDIEF-CIUDSAMLSA-N 0.000 description 1
- ZMUQQMGITUJQTI-CIUDSAMLSA-N Asn-Leu-Asn Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O ZMUQQMGITUJQTI-CIUDSAMLSA-N 0.000 description 1
- GLWFAWNYGWBMOC-SRVKXCTJSA-N Asn-Leu-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O GLWFAWNYGWBMOC-SRVKXCTJSA-N 0.000 description 1
- DJIMLSXHXKWADV-CIUDSAMLSA-N Asn-Leu-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O DJIMLSXHXKWADV-CIUDSAMLSA-N 0.000 description 1
- ORJQQZIXTOYGGH-SRVKXCTJSA-N Asn-Lys-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ORJQQZIXTOYGGH-SRVKXCTJSA-N 0.000 description 1
- COWITDLVHMZSIW-CIUDSAMLSA-N Asn-Lys-Ser Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O COWITDLVHMZSIW-CIUDSAMLSA-N 0.000 description 1
- MYVBTYXSWILFCG-BQBZGAKWSA-N Asn-Met-Gly Chemical compound CSCC[C@@H](C(=O)NCC(=O)O)NC(=O)[C@H](CC(=O)N)N MYVBTYXSWILFCG-BQBZGAKWSA-N 0.000 description 1
- ZVUMKOMKQCANOM-AVGNSLFASA-N Asn-Phe-Gln Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZVUMKOMKQCANOM-AVGNSLFASA-N 0.000 description 1
- RVHGJNGNKGDCPX-KKUMJFAQSA-N Asn-Phe-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N RVHGJNGNKGDCPX-KKUMJFAQSA-N 0.000 description 1
- UYCPJVYQYARFGB-YDHLFZDLSA-N Asn-Phe-Val Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C(C)C)C(O)=O UYCPJVYQYARFGB-YDHLFZDLSA-N 0.000 description 1
- SUIJFTJDTJKSRK-IHRRRGAJSA-N Asn-Pro-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 SUIJFTJDTJKSRK-IHRRRGAJSA-N 0.000 description 1
- XTMZYFMTYJNABC-ZLUOBGJFSA-N Asn-Ser-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N XTMZYFMTYJNABC-ZLUOBGJFSA-N 0.000 description 1
- GZXOUBTUAUAVHD-ACZMJKKPSA-N Asn-Ser-Glu Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CCC(O)=O GZXOUBTUAUAVHD-ACZMJKKPSA-N 0.000 description 1
- HPNDKUOLNRVRAY-BIIVOSGPSA-N Asn-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)N)C(=O)O HPNDKUOLNRVRAY-BIIVOSGPSA-N 0.000 description 1
- QYRMBFWDSFGSFC-OLHMAJIHSA-N Asn-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O QYRMBFWDSFGSFC-OLHMAJIHSA-N 0.000 description 1
- JBDLMLZNDRLDIX-HJGDQZAQSA-N Asn-Thr-Leu Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O JBDLMLZNDRLDIX-HJGDQZAQSA-N 0.000 description 1
- PUUPMDXIHCOPJU-HJGDQZAQSA-N Asn-Thr-Lys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O PUUPMDXIHCOPJU-HJGDQZAQSA-N 0.000 description 1
- KZYSHAMXEBPJBD-JRQIVUDYSA-N Asn-Thr-Tyr Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O KZYSHAMXEBPJBD-JRQIVUDYSA-N 0.000 description 1
- NSTBNYOKCZKOMI-AVGNSLFASA-N Asn-Tyr-Glu Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)NC(=O)[C@H](CC(=O)N)N)O NSTBNYOKCZKOMI-AVGNSLFASA-N 0.000 description 1
- DPSUVAPLRQDWAO-YDHLFZDLSA-N Asn-Tyr-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC(=O)N)N DPSUVAPLRQDWAO-YDHLFZDLSA-N 0.000 description 1
- HBUJSDCLZCXXCW-YDHLFZDLSA-N Asn-Val-Tyr Chemical compound NC(=O)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 HBUJSDCLZCXXCW-YDHLFZDLSA-N 0.000 description 1
- VTYQAQFKMQTKQD-ACZMJKKPSA-N Asp-Ala-Gln Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O VTYQAQFKMQTKQD-ACZMJKKPSA-N 0.000 description 1
- PBVLJOIPOGUQQP-CIUDSAMLSA-N Asp-Ala-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(O)=O PBVLJOIPOGUQQP-CIUDSAMLSA-N 0.000 description 1
- MUWDILPCTSMUHI-ZLUOBGJFSA-N Asp-Asn-Cys Chemical compound C([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N)C(=O)O MUWDILPCTSMUHI-ZLUOBGJFSA-N 0.000 description 1
- UGKZHCBLMLSANF-CIUDSAMLSA-N Asp-Asn-Leu Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O UGKZHCBLMLSANF-CIUDSAMLSA-N 0.000 description 1
- RYEWQKQXRJCHIO-SRVKXCTJSA-N Asp-Asn-Tyr Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 RYEWQKQXRJCHIO-SRVKXCTJSA-N 0.000 description 1
- FANQWNCPNFEPGZ-WHFBIAKZSA-N Asp-Asp-Gly Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O FANQWNCPNFEPGZ-WHFBIAKZSA-N 0.000 description 1
- PZXPWHFYZXTFBI-YUMQZZPRSA-N Asp-Gly-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CC(O)=O PZXPWHFYZXTFBI-YUMQZZPRSA-N 0.000 description 1
- KHGPWGKPYHPOIK-QWRGUYRKSA-N Asp-Gly-Phe Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O KHGPWGKPYHPOIK-QWRGUYRKSA-N 0.000 description 1
- WSGVTKZFVJSJOG-RCOVLWMOSA-N Asp-Gly-Val Chemical compound [H]N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O WSGVTKZFVJSJOG-RCOVLWMOSA-N 0.000 description 1
- LDGUZSIPGSPBJP-XVYDVKMFSA-N Asp-His-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CC(=O)O)N LDGUZSIPGSPBJP-XVYDVKMFSA-N 0.000 description 1
- LIVXPXUVXFRWNY-CIUDSAMLSA-N Asp-Lys-Ala Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O LIVXPXUVXFRWNY-CIUDSAMLSA-N 0.000 description 1
- USNJAPJZSGTTPX-XVSYOHENSA-N Asp-Phe-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(O)=O USNJAPJZSGTTPX-XVSYOHENSA-N 0.000 description 1
- RSMZEHCMIOKNMW-GSSVUCPTSA-N Asp-Thr-Thr Chemical compound [H]N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O RSMZEHCMIOKNMW-GSSVUCPTSA-N 0.000 description 1
- GGBQDSHTXKQSLP-NHCYSSNCSA-N Asp-Val-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CC(=O)O)N GGBQDSHTXKQSLP-NHCYSSNCSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- DZLQXIFVQFTFJY-BYPYZUCNSA-N Cys-Gly-Gly Chemical compound SC[C@H](N)C(=O)NCC(=O)NCC(O)=O DZLQXIFVQFTFJY-BYPYZUCNSA-N 0.000 description 1
- SKSJPIBFNFPTJB-NKWVEPMBSA-N Cys-Gly-Pro Chemical compound C1C[C@@H](N(C1)C(=O)CNC(=O)[C@H](CS)N)C(=O)O SKSJPIBFNFPTJB-NKWVEPMBSA-N 0.000 description 1
- NXQCSPVUPLUTJH-WHFBIAKZSA-N Cys-Ser-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CO)C(=O)NCC(O)=O NXQCSPVUPLUTJH-WHFBIAKZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- NNQHEEQNPQYPGL-FXQIFTODSA-N Gln-Ala-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(O)=O NNQHEEQNPQYPGL-FXQIFTODSA-N 0.000 description 1
- SHERTACNJPYHAR-ACZMJKKPSA-N Gln-Ala-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(N)=O SHERTACNJPYHAR-ACZMJKKPSA-N 0.000 description 1
- SOBBAYVQSNXYPQ-ACZMJKKPSA-N Gln-Asn-Asn Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SOBBAYVQSNXYPQ-ACZMJKKPSA-N 0.000 description 1
- ZPDVKYLJTOFQJV-WDSKDSINSA-N Gln-Asn-Gly Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ZPDVKYLJTOFQJV-WDSKDSINSA-N 0.000 description 1
- RMOCFPBLHAOTDU-ACZMJKKPSA-N Gln-Asn-Ser Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O RMOCFPBLHAOTDU-ACZMJKKPSA-N 0.000 description 1
- LMPBBFWHCRURJD-LAEOZQHASA-N Gln-Asn-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)N)N LMPBBFWHCRURJD-LAEOZQHASA-N 0.000 description 1
- LPYPANUXJGFMGV-FXQIFTODSA-N Gln-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCC(=O)N)N LPYPANUXJGFMGV-FXQIFTODSA-N 0.000 description 1
- AJDMYLOISOCHHC-YVNDNENWSA-N Gln-Gln-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O AJDMYLOISOCHHC-YVNDNENWSA-N 0.000 description 1
- KVXVVDFOZNYYKZ-DCAQKATOSA-N Gln-Gln-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O KVXVVDFOZNYYKZ-DCAQKATOSA-N 0.000 description 1
- MCAVASRGVBVPMX-FXQIFTODSA-N Gln-Glu-Ala Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(O)=O MCAVASRGVBVPMX-FXQIFTODSA-N 0.000 description 1
- ZQPOVSJFBBETHQ-CIUDSAMLSA-N Gln-Glu-Gln Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O ZQPOVSJFBBETHQ-CIUDSAMLSA-N 0.000 description 1
- PNENQZWRFMUZOM-DCAQKATOSA-N Gln-Glu-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(O)=O PNENQZWRFMUZOM-DCAQKATOSA-N 0.000 description 1
- NSNUZSPSADIMJQ-WDSKDSINSA-N Gln-Gly-Asp Chemical compound NC(=O)CC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O NSNUZSPSADIMJQ-WDSKDSINSA-N 0.000 description 1
- GNMQDOGFWYWPNM-LAEOZQHASA-N Gln-Gly-Ile Chemical compound CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@@H](N)CCC(N)=O)C(O)=O GNMQDOGFWYWPNM-LAEOZQHASA-N 0.000 description 1
- QQAPDATZKKTBIY-YUMQZZPRSA-N Gln-Gly-Met Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CCSC)C(O)=O QQAPDATZKKTBIY-YUMQZZPRSA-N 0.000 description 1
- GURIQZQSTBBHRV-SRVKXCTJSA-N Gln-Lys-Arg Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O GURIQZQSTBBHRV-SRVKXCTJSA-N 0.000 description 1
- RWCBJYUPAUTWJD-NHCYSSNCSA-N Gln-Met-Val Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(O)=O RWCBJYUPAUTWJD-NHCYSSNCSA-N 0.000 description 1
- FTTHLXOMDMLKKW-FHWLQOOXSA-N Gln-Phe-Phe Chemical compound C([C@H](NC(=O)[C@H](CCC(N)=O)N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 FTTHLXOMDMLKKW-FHWLQOOXSA-N 0.000 description 1
- LPIKVBWNNVFHCQ-GUBZILKMSA-N Gln-Ser-Leu Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(O)=O LPIKVBWNNVFHCQ-GUBZILKMSA-N 0.000 description 1
- OKQLXOYFUPVEHI-CIUDSAMLSA-N Gln-Ser-Met Chemical compound CSCC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N OKQLXOYFUPVEHI-CIUDSAMLSA-N 0.000 description 1
- BYKZWDGMJLNFJY-XKBZYTNZSA-N Gln-Ser-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)N)N)O BYKZWDGMJLNFJY-XKBZYTNZSA-N 0.000 description 1
- UXXIVIQGOODKQC-NUMRIWBASA-N Gln-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O UXXIVIQGOODKQC-NUMRIWBASA-N 0.000 description 1
- UEILCTONAMOGBR-RWRJDSDZSA-N Gln-Thr-Ile Chemical compound [H]N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O UEILCTONAMOGBR-RWRJDSDZSA-N 0.000 description 1
- RONJIBWTGKVKFY-HTUGSXCWSA-N Gln-Thr-Phe Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CCC(=O)N)N)O RONJIBWTGKVKFY-HTUGSXCWSA-N 0.000 description 1
- QGWXAMDECCKGRU-XVKPBYJWSA-N Gln-Val-Gly Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)CCC(N)=O)C(=O)NCC(O)=O QGWXAMDECCKGRU-XVKPBYJWSA-N 0.000 description 1
- HNAUFGBKJLTWQE-IFFSRLJSSA-N Gln-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(=O)N)N)O HNAUFGBKJLTWQE-IFFSRLJSSA-N 0.000 description 1
- RUFHOVYUYSNDNY-ACZMJKKPSA-N Glu-Ala-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O RUFHOVYUYSNDNY-ACZMJKKPSA-N 0.000 description 1
- GLWXKFRTOHKGIT-ACZMJKKPSA-N Glu-Asn-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O GLWXKFRTOHKGIT-ACZMJKKPSA-N 0.000 description 1
- AFODTOLGSZQDSL-PEFMBERDSA-N Glu-Asn-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CCC(=O)O)N AFODTOLGSZQDSL-PEFMBERDSA-N 0.000 description 1
- ZOXBSICWUDAOHX-GUBZILKMSA-N Glu-Asn-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CCC(O)=O ZOXBSICWUDAOHX-GUBZILKMSA-N 0.000 description 1
- VFZIDQZAEBORGY-GLLZPBPUSA-N Glu-Gln-Thr Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VFZIDQZAEBORGY-GLLZPBPUSA-N 0.000 description 1
- UHVIQGKBMXEVGN-WDSKDSINSA-N Glu-Gly-Asn Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O UHVIQGKBMXEVGN-WDSKDSINSA-N 0.000 description 1
- ZHNHJYYFCGUZNQ-KBIXCLLPSA-N Glu-Ile-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CCC(O)=O ZHNHJYYFCGUZNQ-KBIXCLLPSA-N 0.000 description 1
- IVGJYOOGJLFKQE-AVGNSLFASA-N Glu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CCC(=O)O)N IVGJYOOGJLFKQE-AVGNSLFASA-N 0.000 description 1
- GJBUAAAIZSRCDC-GVXVVHGQSA-N Glu-Leu-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O GJBUAAAIZSRCDC-GVXVVHGQSA-N 0.000 description 1
- ILWHFUZZCFYSKT-AVGNSLFASA-N Glu-Lys-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O ILWHFUZZCFYSKT-AVGNSLFASA-N 0.000 description 1
- HRBYTAIBKPNZKQ-AVGNSLFASA-N Glu-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCC(O)=O HRBYTAIBKPNZKQ-AVGNSLFASA-N 0.000 description 1
- CQAHWYDHKUWYIX-YUMQZZPRSA-N Glu-Pro-Gly Chemical compound OC(=O)CC[C@H](N)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O CQAHWYDHKUWYIX-YUMQZZPRSA-N 0.000 description 1
- JVYNYWXHZWVJEF-NUMRIWBASA-N Glu-Thr-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCC(=O)O)N)O JVYNYWXHZWVJEF-NUMRIWBASA-N 0.000 description 1
- HBMRTXJZQDVRFT-DZKIICNBSA-N Glu-Tyr-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C(C)C)C(O)=O HBMRTXJZQDVRFT-DZKIICNBSA-N 0.000 description 1
- RLFSBAPJTYKSLG-WHFBIAKZSA-N Gly-Ala-Asp Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O RLFSBAPJTYKSLG-WHFBIAKZSA-N 0.000 description 1
- LJPIRKICOISLKN-WHFBIAKZSA-N Gly-Ala-Ser Chemical compound NCC(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O LJPIRKICOISLKN-WHFBIAKZSA-N 0.000 description 1
- XUDLUKYPXQDCRX-BQBZGAKWSA-N Gly-Arg-Asn Chemical compound [H]NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(O)=O XUDLUKYPXQDCRX-BQBZGAKWSA-N 0.000 description 1
- KKBWDNZXYLGJEY-UHFFFAOYSA-N Gly-Arg-Pro Natural products NCC(=O)NC(CCNC(=N)N)C(=O)N1CCCC1C(=O)O KKBWDNZXYLGJEY-UHFFFAOYSA-N 0.000 description 1
- CIMULJZTTOBOPN-WHFBIAKZSA-N Gly-Asn-Asn Chemical compound NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O CIMULJZTTOBOPN-WHFBIAKZSA-N 0.000 description 1
- GVVKYKCOFMMTKZ-WHFBIAKZSA-N Gly-Cys-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)CN GVVKYKCOFMMTKZ-WHFBIAKZSA-N 0.000 description 1
- KTSZUNRRYXPZTK-BQBZGAKWSA-N Gly-Gln-Glu Chemical compound NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O KTSZUNRRYXPZTK-BQBZGAKWSA-N 0.000 description 1
- AQLHORCVPGXDJW-IUCAKERBSA-N Gly-Gln-Lys Chemical compound C(CCN)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)CN AQLHORCVPGXDJW-IUCAKERBSA-N 0.000 description 1
- QPDUVFSVVAOUHE-XVKPBYJWSA-N Gly-Gln-Val Chemical compound CC(C)[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)CN)C(O)=O QPDUVFSVVAOUHE-XVKPBYJWSA-N 0.000 description 1
- HQRHFUYMGCHHJS-LURJTMIESA-N Gly-Gly-Arg Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N HQRHFUYMGCHHJS-LURJTMIESA-N 0.000 description 1
- GDOZQTNZPCUARW-YFKPBYRVSA-N Gly-Gly-Glu Chemical compound NCC(=O)NCC(=O)N[C@H](C(O)=O)CCC(O)=O GDOZQTNZPCUARW-YFKPBYRVSA-N 0.000 description 1
- UQJNXZSSGQIPIQ-FBCQKBJTSA-N Gly-Gly-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)CNC(=O)CN UQJNXZSSGQIPIQ-FBCQKBJTSA-N 0.000 description 1
- SWQALSGKVLYKDT-ZKWXMUAHSA-N Gly-Ile-Ala Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O SWQALSGKVLYKDT-ZKWXMUAHSA-N 0.000 description 1
- HMHRTKOWRUPPNU-RCOVLWMOSA-N Gly-Ile-Gly Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O HMHRTKOWRUPPNU-RCOVLWMOSA-N 0.000 description 1
- HAXARWKYFIIHKD-ZKWXMUAHSA-N Gly-Ile-Ser Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O HAXARWKYFIIHKD-ZKWXMUAHSA-N 0.000 description 1
- COVXELOAORHTND-LSJOCFKGSA-N Gly-Ile-Val Chemical compound NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(O)=O COVXELOAORHTND-LSJOCFKGSA-N 0.000 description 1
- LLZXNUUIBOALNY-QWRGUYRKSA-N Gly-Leu-Lys Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCCN LLZXNUUIBOALNY-QWRGUYRKSA-N 0.000 description 1
- UUYBFNKHOCJCHT-VHSXEESVSA-N Gly-Leu-Pro Chemical compound CC(C)C[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN UUYBFNKHOCJCHT-VHSXEESVSA-N 0.000 description 1
- JPAACTMBBBGAAR-HOTGVXAUSA-N Gly-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)CN)CC(C)C)C(O)=O)=CNC2=C1 JPAACTMBBBGAAR-HOTGVXAUSA-N 0.000 description 1
- LPHQAFLNEHWKFF-QXEWZRGKSA-N Gly-Met-Ile Chemical compound [H]NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LPHQAFLNEHWKFF-QXEWZRGKSA-N 0.000 description 1
- JPVGHHQGKPQYIL-KBPBESRZSA-N Gly-Phe-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=CC=C1 JPVGHHQGKPQYIL-KBPBESRZSA-N 0.000 description 1
- HJARVELKOSZUEW-YUMQZZPRSA-N Gly-Pro-Gln Chemical compound [H]NCC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O HJARVELKOSZUEW-YUMQZZPRSA-N 0.000 description 1
- OHUKZZYSJBKFRR-WHFBIAKZSA-N Gly-Ser-Asp Chemical compound [H]NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(O)=O OHUKZZYSJBKFRR-WHFBIAKZSA-N 0.000 description 1
- SOEGEPHNZOISMT-BYPYZUCNSA-N Gly-Ser-Gly Chemical compound NCC(=O)N[C@@H](CO)C(=O)NCC(O)=O SOEGEPHNZOISMT-BYPYZUCNSA-N 0.000 description 1
- CUVBTVWFVIIDOC-YEPSODPASA-N Gly-Thr-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)CN CUVBTVWFVIIDOC-YEPSODPASA-N 0.000 description 1
- PNUFMLXHOLFRLD-KBPBESRZSA-N Gly-Tyr-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CC=C(O)C=C1 PNUFMLXHOLFRLD-KBPBESRZSA-N 0.000 description 1
- YGHSQRJSHKYUJY-SCZZXKLOSA-N Gly-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)CN YGHSQRJSHKYUJY-SCZZXKLOSA-N 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 1
- BIAKMWKJMQLZOJ-ZKWXMUAHSA-N His-Ala-Ala Chemical compound C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1cnc[nH]1)C(O)=O BIAKMWKJMQLZOJ-ZKWXMUAHSA-N 0.000 description 1
- AFPFGFUGETYOSY-HGNGGELXSA-N His-Ala-Glu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(O)=O AFPFGFUGETYOSY-HGNGGELXSA-N 0.000 description 1
- FLUVGKKRRMLNPU-CQDKDKBSSA-N His-Ala-Phe Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O FLUVGKKRRMLNPU-CQDKDKBSSA-N 0.000 description 1
- FDQYIRHBVVUTJF-ZETCQYMHSA-N His-Gly-Gly Chemical compound [O-]C(=O)CNC(=O)CNC(=O)[C@@H]([NH3+])CC1=CN=CN1 FDQYIRHBVVUTJF-ZETCQYMHSA-N 0.000 description 1
- PGTISAJTWZPFGN-PEXQALLHSA-N His-Gly-Ile Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(O)=O PGTISAJTWZPFGN-PEXQALLHSA-N 0.000 description 1
- MPXGJGBXCRQQJE-MXAVVETBSA-N His-Ile-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O MPXGJGBXCRQQJE-MXAVVETBSA-N 0.000 description 1
- VSZALHITQINTGC-GHCJXIJMSA-N Ile-Ala-Asp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)O)N VSZALHITQINTGC-GHCJXIJMSA-N 0.000 description 1
- YPWHUFAAMNHMGS-QSFUFRPTSA-N Ile-Ala-His Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N YPWHUFAAMNHMGS-QSFUFRPTSA-N 0.000 description 1
- QADCTXFNLZBZAB-GHCJXIJMSA-N Ile-Asn-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](C)C(=O)O)N QADCTXFNLZBZAB-GHCJXIJMSA-N 0.000 description 1
- NCSIQAFSIPHVAN-IUKAMOBKSA-N Ile-Asn-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N NCSIQAFSIPHVAN-IUKAMOBKSA-N 0.000 description 1
- NKRJALPCDNXULF-BYULHYEWSA-N Ile-Asp-Gly Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O NKRJALPCDNXULF-BYULHYEWSA-N 0.000 description 1
- GYAFMRQGWHXMII-IUKAMOBKSA-N Ile-Asp-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N GYAFMRQGWHXMII-IUKAMOBKSA-N 0.000 description 1
- LKACSKJPTFSBHR-MNXVOIDGSA-N Ile-Gln-Lys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)O)N LKACSKJPTFSBHR-MNXVOIDGSA-N 0.000 description 1
- JRYQSFOFUFXPTB-RWRJDSDZSA-N Ile-Gln-Thr Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)N JRYQSFOFUFXPTB-RWRJDSDZSA-N 0.000 description 1
- DVRDRICMWUSCBN-UKJIMTQDSA-N Ile-Gln-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](C(C)C)C(=O)O)N DVRDRICMWUSCBN-UKJIMTQDSA-N 0.000 description 1
- BEWFWZRGBDVXRP-PEFMBERDSA-N Ile-Glu-Asn Chemical compound [H]N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O BEWFWZRGBDVXRP-PEFMBERDSA-N 0.000 description 1
- KFVUBLZRFSVDGO-BYULHYEWSA-N Ile-Gly-Asp Chemical compound CC[C@H](C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CC(O)=O KFVUBLZRFSVDGO-BYULHYEWSA-N 0.000 description 1
- MQFGXJNSUJTXDT-QSFUFRPTSA-N Ile-Gly-Ile Chemical compound N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)O MQFGXJNSUJTXDT-QSFUFRPTSA-N 0.000 description 1
- BBQABUDWDUKJMB-LZXPERKUSA-N Ile-Ile-Ile Chemical compound CC[C@H](C)[C@H]([NH3+])C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C([O-])=O BBQABUDWDUKJMB-LZXPERKUSA-N 0.000 description 1
- YSGBJIQXTIVBHZ-AJNGGQMLSA-N Ile-Lys-Leu Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O YSGBJIQXTIVBHZ-AJNGGQMLSA-N 0.000 description 1
- AKOYRLRUFBZOSP-BJDJZHNGSA-N Ile-Lys-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)O)N AKOYRLRUFBZOSP-BJDJZHNGSA-N 0.000 description 1
- NLZVTPYXYXMCIP-XUXIUFHCSA-N Ile-Pro-Lys Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCCN)C(O)=O NLZVTPYXYXMCIP-XUXIUFHCSA-N 0.000 description 1
- KTNGVMMGIQWIDV-OSUNSFLBSA-N Ile-Pro-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(O)=O KTNGVMMGIQWIDV-OSUNSFLBSA-N 0.000 description 1
- PXKACEXYLPBMAD-JBDRJPRFSA-N Ile-Ser-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PXKACEXYLPBMAD-JBDRJPRFSA-N 0.000 description 1
- RKQAYOWLSFLJEE-SVSWQMSJSA-N Ile-Thr-Cys Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)O)N RKQAYOWLSFLJEE-SVSWQMSJSA-N 0.000 description 1
- NURNJECQNNCRBK-FLBSBUHZSA-N Ile-Thr-Thr Chemical compound CC[C@H](C)[C@H](N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O NURNJECQNNCRBK-FLBSBUHZSA-N 0.000 description 1
- JZBVBOKASHNXAD-NAKRPEOUSA-N Ile-Val-Ser Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(=O)O)N JZBVBOKASHNXAD-NAKRPEOUSA-N 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- FADYJNXDPBKVCA-UHFFFAOYSA-N L-Phenylalanyl-L-lysin Natural products NCCCCC(C(O)=O)NC(=O)C(N)CC1=CC=CC=C1 FADYJNXDPBKVCA-UHFFFAOYSA-N 0.000 description 1
- RCFDOSNHHZGBOY-UHFFFAOYSA-N L-isoleucyl-L-alanine Natural products CCC(C)C(N)C(=O)NC(C)C(O)=O RCFDOSNHHZGBOY-UHFFFAOYSA-N 0.000 description 1
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- LJHGALIOHLRRQN-DCAQKATOSA-N Leu-Ala-Arg Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N LJHGALIOHLRRQN-DCAQKATOSA-N 0.000 description 1
- CZCSUZMIRKFFFA-CIUDSAMLSA-N Leu-Ala-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O CZCSUZMIRKFFFA-CIUDSAMLSA-N 0.000 description 1
- MJOZZTKJZQFKDK-GUBZILKMSA-N Leu-Ala-Gln Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCC(N)=O MJOZZTKJZQFKDK-GUBZILKMSA-N 0.000 description 1
- XBBKIIGCUMBKCO-JXUBOQSCSA-N Leu-Ala-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XBBKIIGCUMBKCO-JXUBOQSCSA-N 0.000 description 1
- JKGHDYGZRDWHGA-SRVKXCTJSA-N Leu-Asn-Leu Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JKGHDYGZRDWHGA-SRVKXCTJSA-N 0.000 description 1
- OGCQGUIWMSBHRZ-CIUDSAMLSA-N Leu-Asn-Ser Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(O)=O OGCQGUIWMSBHRZ-CIUDSAMLSA-N 0.000 description 1
- CLVUXCBGKUECIT-HJGDQZAQSA-N Leu-Asp-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CLVUXCBGKUECIT-HJGDQZAQSA-N 0.000 description 1
- IASQBRJGRVXNJI-YUMQZZPRSA-N Leu-Cys-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)NCC(O)=O IASQBRJGRVXNJI-YUMQZZPRSA-N 0.000 description 1
- CIVKXGPFXDIQBV-WDCWCFNPSA-N Leu-Gln-Thr Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O CIVKXGPFXDIQBV-WDCWCFNPSA-N 0.000 description 1
- FMEICTQWUKNAGC-YUMQZZPRSA-N Leu-Gly-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O FMEICTQWUKNAGC-YUMQZZPRSA-N 0.000 description 1
- APFJUBGRZGMQFF-QWRGUYRKSA-N Leu-Gly-Lys Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCCCN APFJUBGRZGMQFF-QWRGUYRKSA-N 0.000 description 1
- POZULHZYLPGXMR-ONGXEEELSA-N Leu-Gly-Val Chemical compound CC(C)C[C@H](N)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O POZULHZYLPGXMR-ONGXEEELSA-N 0.000 description 1
- USLNHQZCDQJBOV-ZPFDUUQYSA-N Leu-Ile-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O USLNHQZCDQJBOV-ZPFDUUQYSA-N 0.000 description 1
- IAJFFZORSWOZPQ-SRVKXCTJSA-N Leu-Leu-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IAJFFZORSWOZPQ-SRVKXCTJSA-N 0.000 description 1
- LXKNSJLSGPNHSK-KKUMJFAQSA-N Leu-Leu-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)O)N LXKNSJLSGPNHSK-KKUMJFAQSA-N 0.000 description 1
- IEWBEPKLKUXQBU-VOAKCMCISA-N Leu-Leu-Thr Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IEWBEPKLKUXQBU-VOAKCMCISA-N 0.000 description 1
- WXUOJXIGOPMDJM-SRVKXCTJSA-N Leu-Lys-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O WXUOJXIGOPMDJM-SRVKXCTJSA-N 0.000 description 1
- FKQPWMZLIIATBA-AJNGGQMLSA-N Leu-Lys-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FKQPWMZLIIATBA-AJNGGQMLSA-N 0.000 description 1
- BIZNDKMFQHDOIE-KKUMJFAQSA-N Leu-Phe-Asn Chemical compound CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(O)=O)CC1=CC=CC=C1 BIZNDKMFQHDOIE-KKUMJFAQSA-N 0.000 description 1
- INCJJHQRZGQLFC-KBPBESRZSA-N Leu-Phe-Gly Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)NCC(O)=O INCJJHQRZGQLFC-KBPBESRZSA-N 0.000 description 1
- XOWMDXHFSBCAKQ-SRVKXCTJSA-N Leu-Ser-Leu Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(O)=O)CC(C)C XOWMDXHFSBCAKQ-SRVKXCTJSA-N 0.000 description 1
- AMSSKPUHBUQBOQ-SRVKXCTJSA-N Leu-Ser-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)O)N AMSSKPUHBUQBOQ-SRVKXCTJSA-N 0.000 description 1
- WUHBLPVELFTPQK-KKUMJFAQSA-N Leu-Tyr-Asn Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O WUHBLPVELFTPQK-KKUMJFAQSA-N 0.000 description 1
- VKVDRTGWLVZJOM-DCAQKATOSA-N Leu-Val-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O VKVDRTGWLVZJOM-DCAQKATOSA-N 0.000 description 1
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 1
- SWWCDAGDQHTKIE-RHYQMDGZSA-N Lys-Arg-Thr Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWWCDAGDQHTKIE-RHYQMDGZSA-N 0.000 description 1
- ABHIXYDMILIUKV-CIUDSAMLSA-N Lys-Asn-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O ABHIXYDMILIUKV-CIUDSAMLSA-N 0.000 description 1
- PGBPWPTUOSCNLE-JYJNAYRXSA-N Lys-Gln-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CCCCN)N PGBPWPTUOSCNLE-JYJNAYRXSA-N 0.000 description 1
- QZONCCHVHCOBSK-YUMQZZPRSA-N Lys-Gly-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(O)=O QZONCCHVHCOBSK-YUMQZZPRSA-N 0.000 description 1
- DTUZCYRNEJDKSR-NHCYSSNCSA-N Lys-Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN DTUZCYRNEJDKSR-NHCYSSNCSA-N 0.000 description 1
- FHIAJWBDZVHLAH-YUMQZZPRSA-N Lys-Gly-Ser Chemical compound NCCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CO)C(O)=O FHIAJWBDZVHLAH-YUMQZZPRSA-N 0.000 description 1
- KYNNSEJZFVCDIV-ZPFDUUQYSA-N Lys-Ile-Asn Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O KYNNSEJZFVCDIV-ZPFDUUQYSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- RIJCHEVHFWMDKD-SRVKXCTJSA-N Lys-Lys-Asn Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RIJCHEVHFWMDKD-SRVKXCTJSA-N 0.000 description 1
- HVAUKHLDSDDROB-KKUMJFAQSA-N Lys-Lys-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O HVAUKHLDSDDROB-KKUMJFAQSA-N 0.000 description 1
- WBSCNDJQPKSPII-KKUMJFAQSA-N Lys-Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O WBSCNDJQPKSPII-KKUMJFAQSA-N 0.000 description 1
- GOVDTWNJCBRRBJ-DCAQKATOSA-N Lys-Met-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](CCCCN)N GOVDTWNJCBRRBJ-DCAQKATOSA-N 0.000 description 1
- WWEWGPOLIJXGNX-XUXIUFHCSA-N Lys-Met-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)N WWEWGPOLIJXGNX-XUXIUFHCSA-N 0.000 description 1
- PDIDTSZKKFEDMB-UWVGGRQHSA-N Lys-Pro-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)NCC(O)=O PDIDTSZKKFEDMB-UWVGGRQHSA-N 0.000 description 1
- WQDKIVRHTQYJSN-DCAQKATOSA-N Lys-Ser-Arg Chemical compound C(CCN)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N WQDKIVRHTQYJSN-DCAQKATOSA-N 0.000 description 1
- SBQDRNOLGSYHQA-YUMQZZPRSA-N Lys-Ser-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SBQDRNOLGSYHQA-YUMQZZPRSA-N 0.000 description 1
- DIBZLYZXTSVGLN-CIUDSAMLSA-N Lys-Ser-Ser Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(O)=O DIBZLYZXTSVGLN-CIUDSAMLSA-N 0.000 description 1
- YKBSXQFZWFXFIB-VOAKCMCISA-N Lys-Thr-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CCCCN)C(O)=O YKBSXQFZWFXFIB-VOAKCMCISA-N 0.000 description 1
- VHTOGMKQXXJOHG-RHYQMDGZSA-N Lys-Thr-Val Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(O)=O VHTOGMKQXXJOHG-RHYQMDGZSA-N 0.000 description 1
- CFOLERIRBUAYAD-HOCLYGCPSA-N Lys-Trp-Gly Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)NCC(O)=O CFOLERIRBUAYAD-HOCLYGCPSA-N 0.000 description 1
- ZVZRQKJOQQAFCF-ULQDDVLXSA-N Lys-Tyr-Arg Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O ZVZRQKJOQQAFCF-ULQDDVLXSA-N 0.000 description 1
- VKCPHIOZDWUFSW-ONGXEEELSA-N Lys-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CCCCN VKCPHIOZDWUFSW-ONGXEEELSA-N 0.000 description 1
- OZVXDDFYCQOPFD-XQQFMLRXSA-N Lys-Val-Pro Chemical compound CC(C)[C@@H](C(=O)N1CCC[C@@H]1C(=O)O)NC(=O)[C@H](CCCCN)N OZVXDDFYCQOPFD-XQQFMLRXSA-N 0.000 description 1
- IKXQOBUBZSOWDY-AVGNSLFASA-N Lys-Val-Val Chemical compound CC(C)[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CCCCN)N IKXQOBUBZSOWDY-AVGNSLFASA-N 0.000 description 1
- 241000282560 Macaca mulatta Species 0.000 description 1
- FRWZTWWOORIIBA-FXQIFTODSA-N Met-Asn-Asn Chemical compound CSCC[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N FRWZTWWOORIIBA-FXQIFTODSA-N 0.000 description 1
- ACYHZNZHIZWLQF-BQBZGAKWSA-N Met-Asn-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(O)=O ACYHZNZHIZWLQF-BQBZGAKWSA-N 0.000 description 1
- YNOVBMBQSQTLFM-DCAQKATOSA-N Met-Asn-Leu Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O YNOVBMBQSQTLFM-DCAQKATOSA-N 0.000 description 1
- OHMKUHXCDSCOMT-QXEWZRGKSA-N Met-Asn-Val Chemical compound [H]N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(O)=O OHMKUHXCDSCOMT-QXEWZRGKSA-N 0.000 description 1
- AVTWKENDGGUWDC-BQBZGAKWSA-N Met-Cys-Gly Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CS)C(=O)NCC(O)=O AVTWKENDGGUWDC-BQBZGAKWSA-N 0.000 description 1
- OGAZPKJHHZPYFK-GARJFASQSA-N Met-Glu-Pro Chemical compound CSCC[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N1CCC[C@@H]1C(=O)O)N OGAZPKJHHZPYFK-GARJFASQSA-N 0.000 description 1
- IUYCGMNKIZDRQI-BQBZGAKWSA-N Met-Gly-Ala Chemical compound CSCC[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O IUYCGMNKIZDRQI-BQBZGAKWSA-N 0.000 description 1
- BMHIFARYXOJDLD-WPRPVWTQSA-N Met-Gly-Val Chemical compound [H]N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O BMHIFARYXOJDLD-WPRPVWTQSA-N 0.000 description 1
- HAQLBBVZAGMESV-IHRRRGAJSA-N Met-Lys-Lys Chemical compound CSCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O HAQLBBVZAGMESV-IHRRRGAJSA-N 0.000 description 1
- NLDXSXDCNZIQCN-ULQDDVLXSA-N Met-Phe-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CCSC)CC1=CC=CC=C1 NLDXSXDCNZIQCN-ULQDDVLXSA-N 0.000 description 1
- IIHMNTBFPMRJCN-RCWTZXSCSA-N Met-Val-Thr Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O IIHMNTBFPMRJCN-RCWTZXSCSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010002311 N-glycylglutamic acid Proteins 0.000 description 1
- 108010066427 N-valyltryptophan Proteins 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- UHRNIXJAGGLKHP-DLOVCJGASA-N Phe-Ala-Ser Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O UHRNIXJAGGLKHP-DLOVCJGASA-N 0.000 description 1
- NOFBJKKOPKJDCO-KKXDTOCCSA-N Phe-Ala-Tyr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O NOFBJKKOPKJDCO-KKXDTOCCSA-N 0.000 description 1
- HTTYNOXBBOWZTB-SRVKXCTJSA-N Phe-Asn-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N HTTYNOXBBOWZTB-SRVKXCTJSA-N 0.000 description 1
- WGXOKDLDIWSOCV-MELADBBJSA-N Phe-Asn-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC2=CC=CC=C2)N)C(=O)O WGXOKDLDIWSOCV-MELADBBJSA-N 0.000 description 1
- CUMXHKAOHNWRFQ-BZSNNMDCSA-N Phe-Asp-Tyr Chemical compound C([C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C1=CC=CC=C1 CUMXHKAOHNWRFQ-BZSNNMDCSA-N 0.000 description 1
- GDBOREPXIRKSEQ-FHWLQOOXSA-N Phe-Gln-Phe Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O GDBOREPXIRKSEQ-FHWLQOOXSA-N 0.000 description 1
- PSKRILMFHNIUAO-JYJNAYRXSA-N Phe-Glu-Lys Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCCCN)C(=O)O)N PSKRILMFHNIUAO-JYJNAYRXSA-N 0.000 description 1
- JJHVFCUWLSKADD-ONGXEEELSA-N Phe-Gly-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H](C)C(O)=O JJHVFCUWLSKADD-ONGXEEELSA-N 0.000 description 1
- YYKZDTVQHTUKDW-RYUDHWBXSA-N Phe-Gly-Gln Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)NCC(=O)N[C@@H](CCC(=O)N)C(=O)O)N YYKZDTVQHTUKDW-RYUDHWBXSA-N 0.000 description 1
- QPVFUAUFEBPIPT-CDMKHQONSA-N Phe-Gly-Thr Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(O)=O QPVFUAUFEBPIPT-CDMKHQONSA-N 0.000 description 1
- WKTSCAXSYITIJJ-PCBIJLKTSA-N Phe-Ile-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(O)=O WKTSCAXSYITIJJ-PCBIJLKTSA-N 0.000 description 1
- SMFGCTXUBWEPKM-KBPBESRZSA-N Phe-Leu-Gly Chemical compound OC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC1=CC=CC=C1 SMFGCTXUBWEPKM-KBPBESRZSA-N 0.000 description 1
- MSHZERMPZKCODG-ACRUOGEOSA-N Phe-Leu-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 MSHZERMPZKCODG-ACRUOGEOSA-N 0.000 description 1
- RMKGXGPQIPLTFC-KKUMJFAQSA-N Phe-Lys-Asn Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O RMKGXGPQIPLTFC-KKUMJFAQSA-N 0.000 description 1
- OWSLLRKCHLTUND-BZSNNMDCSA-N Phe-Phe-Asn Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H](CC(=O)N)C(=O)O)N OWSLLRKCHLTUND-BZSNNMDCSA-N 0.000 description 1
- KAJLHCWRWDSROH-BZSNNMDCSA-N Phe-Phe-Asp Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(O)=O)C(O)=O)C1=CC=CC=C1 KAJLHCWRWDSROH-BZSNNMDCSA-N 0.000 description 1
- GMWNQSGWWGKTSF-LFSVMHDDSA-N Phe-Thr-Ala Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O GMWNQSGWWGKTSF-LFSVMHDDSA-N 0.000 description 1
- XNQMZHLAYFWSGJ-HTUGSXCWSA-N Phe-Thr-Glu Chemical compound [H]N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(O)=O XNQMZHLAYFWSGJ-HTUGSXCWSA-N 0.000 description 1
- NJONQBYLTANINY-IHPCNDPISA-N Phe-Trp-Asn Chemical compound N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(N)=O)C(O)=O NJONQBYLTANINY-IHPCNDPISA-N 0.000 description 1
- MHNBYYFXWDUGBW-RPTUDFQQSA-N Phe-Tyr-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](CC2=CC=CC=C2)N)O MHNBYYFXWDUGBW-RPTUDFQQSA-N 0.000 description 1
- MWQXFDIQXIXPMS-UNQGMJICSA-N Phe-Val-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC1=CC=CC=C1)N)O MWQXFDIQXIXPMS-UNQGMJICSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- UVKNEILZSJMKSR-FXQIFTODSA-N Pro-Asn-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]1CCCN1 UVKNEILZSJMKSR-FXQIFTODSA-N 0.000 description 1
- VOHFZDSRPZLXLH-IHRRRGAJSA-N Pro-Asn-Phe Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O VOHFZDSRPZLXLH-IHRRRGAJSA-N 0.000 description 1
- SWXSLPHTJVAWDF-VEVYYDQMSA-N Pro-Asn-Thr Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SWXSLPHTJVAWDF-VEVYYDQMSA-N 0.000 description 1
- ZCXQTRXYZOSGJR-FXQIFTODSA-N Pro-Asp-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O ZCXQTRXYZOSGJR-FXQIFTODSA-N 0.000 description 1
- DIFXZGPHVCIVSQ-CIUDSAMLSA-N Pro-Gln-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(O)=O DIFXZGPHVCIVSQ-CIUDSAMLSA-N 0.000 description 1
- UREQLMJCKFLLHM-NAKRPEOUSA-N Pro-Ile-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(O)=O UREQLMJCKFLLHM-NAKRPEOUSA-N 0.000 description 1
- DWGFLKQSGRUQTI-IHRRRGAJSA-N Pro-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1 DWGFLKQSGRUQTI-IHRRRGAJSA-N 0.000 description 1
- WLJYLAQSUSIQNH-GUBZILKMSA-N Pro-Met-Ser Chemical compound CSCC[C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@@H]1CCCN1 WLJYLAQSUSIQNH-GUBZILKMSA-N 0.000 description 1
- LGMBKOAPPTYKLC-JYJNAYRXSA-N Pro-Phe-Arg Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(=N)N)C(O)=O)NC(=O)[C@H]1NCCC1)C1=CC=CC=C1 LGMBKOAPPTYKLC-JYJNAYRXSA-N 0.000 description 1
- LEIKGVHQTKHOLM-IUCAKERBSA-N Pro-Pro-Gly Chemical compound OC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1 LEIKGVHQTKHOLM-IUCAKERBSA-N 0.000 description 1
- POQFNPILEQEODH-FXQIFTODSA-N Pro-Ser-Ala Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(O)=O POQFNPILEQEODH-FXQIFTODSA-N 0.000 description 1
- CHYAYDLYYIJCKY-OSUNSFLBSA-N Pro-Thr-Ile Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O CHYAYDLYYIJCKY-OSUNSFLBSA-N 0.000 description 1
- VPBQDHMASPJHGY-JYJNAYRXSA-N Pro-Trp-Ser Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CNC3=CC=CC=C32)C(=O)N[C@@H](CO)C(=O)O VPBQDHMASPJHGY-JYJNAYRXSA-N 0.000 description 1
- DYJTXTCEXMCPBF-UFYCRDLUSA-N Pro-Tyr-Phe Chemical compound C1C[C@H](NC1)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CC3=CC=CC=C3)C(=O)O DYJTXTCEXMCPBF-UFYCRDLUSA-N 0.000 description 1
- FUOGXAQMNJMBFG-WPRPVWTQSA-N Pro-Val-Gly Chemical compound OC(=O)CNC(=O)[C@H](C(C)C)NC(=O)[C@@H]1CCCN1 FUOGXAQMNJMBFG-WPRPVWTQSA-N 0.000 description 1
- 101710093543 Probable non-specific lipid-transfer protein Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010067470 Rotavirus infection Diseases 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MWMKFWJYRRGXOR-ZLUOBGJFSA-N Ser-Ala-Asn Chemical compound N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)O)CC(N)=O)C)CO MWMKFWJYRRGXOR-ZLUOBGJFSA-N 0.000 description 1
- LVVBAKCGXXUHFO-ZLUOBGJFSA-N Ser-Ala-Asp Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(O)=O LVVBAKCGXXUHFO-ZLUOBGJFSA-N 0.000 description 1
- WTWGOQRNRFHFQD-JBDRJPRFSA-N Ser-Ala-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O WTWGOQRNRFHFQD-JBDRJPRFSA-N 0.000 description 1
- WTUJZHKANPDPIN-CIUDSAMLSA-N Ser-Ala-Lys Chemical compound C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)O)NC(=O)[C@H](CO)N WTUJZHKANPDPIN-CIUDSAMLSA-N 0.000 description 1
- ZXLUWXWISXIFIX-ACZMJKKPSA-N Ser-Asn-Glu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(O)=O ZXLUWXWISXIFIX-ACZMJKKPSA-N 0.000 description 1
- VAIZFHMTBFYJIA-ACZMJKKPSA-N Ser-Asp-Gln Chemical compound OC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(O)=O)CCC(N)=O VAIZFHMTBFYJIA-ACZMJKKPSA-N 0.000 description 1
- MMAPOBOTRUVNKJ-ZLUOBGJFSA-N Ser-Asp-Ser Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)O)NC(=O)[C@H](CO)N)C(=O)O MMAPOBOTRUVNKJ-ZLUOBGJFSA-N 0.000 description 1
- SWSRFJZZMNLMLY-ZKWXMUAHSA-N Ser-Asp-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(O)=O SWSRFJZZMNLMLY-ZKWXMUAHSA-N 0.000 description 1
- CRZRTKAVUUGKEQ-ACZMJKKPSA-N Ser-Gln-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(O)=O CRZRTKAVUUGKEQ-ACZMJKKPSA-N 0.000 description 1
- SQBLRDDJTUJDMV-ACZMJKKPSA-N Ser-Glu-Asn Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O SQBLRDDJTUJDMV-ACZMJKKPSA-N 0.000 description 1
- SVWQEIRZHHNBIO-WHFBIAKZSA-N Ser-Gly-Cys Chemical compound [H]N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CS)C(O)=O SVWQEIRZHHNBIO-WHFBIAKZSA-N 0.000 description 1
- GJFYFGOEWLDQGW-GUBZILKMSA-N Ser-Leu-Gln Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CO)N GJFYFGOEWLDQGW-GUBZILKMSA-N 0.000 description 1
- MUJQWSAWLLRJCE-KATARQTJSA-N Ser-Leu-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O MUJQWSAWLLRJCE-KATARQTJSA-N 0.000 description 1
- LRWBCWGEUCKDTN-BJDJZHNGSA-N Ser-Lys-Ile Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O LRWBCWGEUCKDTN-BJDJZHNGSA-N 0.000 description 1
- PMCMLDNPAZUYGI-DCAQKATOSA-N Ser-Lys-Val Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(O)=O PMCMLDNPAZUYGI-DCAQKATOSA-N 0.000 description 1
- UPLYXVPQLJVWMM-KKUMJFAQSA-N Ser-Phe-Leu Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)C(O)=O UPLYXVPQLJVWMM-KKUMJFAQSA-N 0.000 description 1
- TVPQRPNBYCRRLL-IHRRRGAJSA-N Ser-Phe-Met Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCSC)C(O)=O TVPQRPNBYCRRLL-IHRRRGAJSA-N 0.000 description 1
- RRVFEDGUXSYWOW-BZSNNMDCSA-N Ser-Phe-Phe Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O RRVFEDGUXSYWOW-BZSNNMDCSA-N 0.000 description 1
- ADJDNJCSPNFFPI-FXQIFTODSA-N Ser-Pro-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CO ADJDNJCSPNFFPI-FXQIFTODSA-N 0.000 description 1
- WNDUPCKKKGSKIQ-CIUDSAMLSA-N Ser-Pro-Gln Chemical compound OC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(O)=O WNDUPCKKKGSKIQ-CIUDSAMLSA-N 0.000 description 1
- FZXOPYUEQGDGMS-ACZMJKKPSA-N Ser-Ser-Gln Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(O)=O FZXOPYUEQGDGMS-ACZMJKKPSA-N 0.000 description 1
- SNXUIBACCONSOH-BWBBJGPYSA-N Ser-Thr-Ser Chemical compound OC[C@H](N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(O)=O SNXUIBACCONSOH-BWBBJGPYSA-N 0.000 description 1
- VLMIUSLQONKLDV-HEIBUPTGSA-N Ser-Thr-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O VLMIUSLQONKLDV-HEIBUPTGSA-N 0.000 description 1
- PIQRHJQWEPWFJG-UWJYBYFXSA-N Ser-Tyr-Ala Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](C)C(O)=O PIQRHJQWEPWFJG-UWJYBYFXSA-N 0.000 description 1
- MFQMZDPAZRZAPV-NAKRPEOUSA-N Ser-Val-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N MFQMZDPAZRZAPV-NAKRPEOUSA-N 0.000 description 1
- SIEBDTCABMZCLF-XGEHTFHBSA-N Ser-Val-Thr Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O SIEBDTCABMZCLF-XGEHTFHBSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- DFTCYYILCSQGIZ-GCJQMDKQSA-N Thr-Ala-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(O)=O DFTCYYILCSQGIZ-GCJQMDKQSA-N 0.000 description 1
- YRNBANYVJJBGDI-VZFHVOOUSA-N Thr-Ala-Cys Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CS)C(=O)O)N)O YRNBANYVJJBGDI-VZFHVOOUSA-N 0.000 description 1
- TYVAWPFQYFPSBR-BFHQHQDPSA-N Thr-Ala-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(=O)NCC(O)=O TYVAWPFQYFPSBR-BFHQHQDPSA-N 0.000 description 1
- TWLMXDWFVNEFFK-FJXKBIBVSA-N Thr-Arg-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O TWLMXDWFVNEFFK-FJXKBIBVSA-N 0.000 description 1
- VIBXMCZWVUOZLA-OLHMAJIHSA-N Thr-Asn-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O VIBXMCZWVUOZLA-OLHMAJIHSA-N 0.000 description 1
- SKHPKKYKDYULDH-HJGDQZAQSA-N Thr-Asn-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O SKHPKKYKDYULDH-HJGDQZAQSA-N 0.000 description 1
- JBHMLZSKIXMVFS-XVSYOHENSA-N Thr-Asn-Phe Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O JBHMLZSKIXMVFS-XVSYOHENSA-N 0.000 description 1
- LXWZOMSOUAMOIA-JIOCBJNQSA-N Thr-Asn-Pro Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N1CCC[C@@H]1C(=O)O)N)O LXWZOMSOUAMOIA-JIOCBJNQSA-N 0.000 description 1
- PQLXHSACXPGWPD-GSSVUCPTSA-N Thr-Asn-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O PQLXHSACXPGWPD-GSSVUCPTSA-N 0.000 description 1
- ODSAPYVQSLDRSR-LKXGYXEUSA-N Thr-Cys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(O)=O ODSAPYVQSLDRSR-LKXGYXEUSA-N 0.000 description 1
- MMTOHPRBJKEZHT-BWBBJGPYSA-N Thr-Cys-Ser Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](CO)C(O)=O MMTOHPRBJKEZHT-BWBBJGPYSA-N 0.000 description 1
- VUVCRYXYUUPGSB-GLLZPBPUSA-N Thr-Gln-Glu Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N)O VUVCRYXYUUPGSB-GLLZPBPUSA-N 0.000 description 1
- UHBPFYOQQPFKQR-JHEQGTHGSA-N Thr-Gln-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(O)=O UHBPFYOQQPFKQR-JHEQGTHGSA-N 0.000 description 1
- DXNUZQGVOMCGNS-SWRJLBSHSA-N Thr-Gln-Trp Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N)O DXNUZQGVOMCGNS-SWRJLBSHSA-N 0.000 description 1
- CQNFRKAKGDSJFR-NUMRIWBASA-N Thr-Glu-Asn Chemical compound C[C@H]([C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N)O CQNFRKAKGDSJFR-NUMRIWBASA-N 0.000 description 1
- JMGJDTNUMAZNLX-RWRJDSDZSA-N Thr-Glu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O JMGJDTNUMAZNLX-RWRJDSDZSA-N 0.000 description 1
- XOTBWOCSLMBGMF-SUSMZKCASA-N Thr-Glu-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XOTBWOCSLMBGMF-SUSMZKCASA-N 0.000 description 1
- KBBRNEDOYWMIJP-KYNKHSRBSA-N Thr-Gly-Thr Chemical compound C[C@H]([C@@H](C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)O)N)O KBBRNEDOYWMIJP-KYNKHSRBSA-N 0.000 description 1
- JKGGPMOUIAAJAA-YEPSODPASA-N Thr-Gly-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](C(C)C)C(O)=O JKGGPMOUIAAJAA-YEPSODPASA-N 0.000 description 1
- GXUWHVZYDAHFSV-FLBSBUHZSA-N Thr-Ile-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(O)=O GXUWHVZYDAHFSV-FLBSBUHZSA-N 0.000 description 1
- IMDMLDSVUSMAEJ-HJGDQZAQSA-N Thr-Leu-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O IMDMLDSVUSMAEJ-HJGDQZAQSA-N 0.000 description 1
- FLPZMPOZGYPBEN-PPCPHDFISA-N Thr-Leu-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O FLPZMPOZGYPBEN-PPCPHDFISA-N 0.000 description 1
- KZSYAEWQMJEGRZ-RHYQMDGZSA-N Thr-Leu-Val Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(O)=O KZSYAEWQMJEGRZ-RHYQMDGZSA-N 0.000 description 1
- BDGBHYCAZJPLHX-HJGDQZAQSA-N Thr-Lys-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(O)=O BDGBHYCAZJPLHX-HJGDQZAQSA-N 0.000 description 1
- SPVHQURZJCUDQC-VOAKCMCISA-N Thr-Lys-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O SPVHQURZJCUDQC-VOAKCMCISA-N 0.000 description 1
- PCMDGXKXVMBIFP-VEVYYDQMSA-N Thr-Met-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(O)=O PCMDGXKXVMBIFP-VEVYYDQMSA-N 0.000 description 1
- WVVOFCVMHAXGLE-LFSVMHDDSA-N Thr-Phe-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H](C)C(O)=O WVVOFCVMHAXGLE-LFSVMHDDSA-N 0.000 description 1
- STUAPCLEDMKXKL-LKXGYXEUSA-N Thr-Ser-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(O)=O STUAPCLEDMKXKL-LKXGYXEUSA-N 0.000 description 1
- SGAOHNPSEPVAFP-ZDLURKLDSA-N Thr-Ser-Gly Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)NCC(O)=O SGAOHNPSEPVAFP-ZDLURKLDSA-N 0.000 description 1
- NQQMWWVVGIXUOX-SVSWQMSJSA-N Thr-Ser-Ile Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O NQQMWWVVGIXUOX-SVSWQMSJSA-N 0.000 description 1
- NDZYTIMDOZMECO-SHGPDSBTSA-N Thr-Thr-Ala Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C)C(O)=O NDZYTIMDOZMECO-SHGPDSBTSA-N 0.000 description 1
- QYDKSNXSBXZPFK-ZJDVBMNYSA-N Thr-Thr-Arg Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O QYDKSNXSBXZPFK-ZJDVBMNYSA-N 0.000 description 1
- BBPCSGKKPJUYRB-UVOCVTCTSA-N Thr-Thr-Leu Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O BBPCSGKKPJUYRB-UVOCVTCTSA-N 0.000 description 1
- NJGMALCNYAMYCB-JRQIVUDYSA-N Thr-Tyr-Asn Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(O)=O NJGMALCNYAMYCB-JRQIVUDYSA-N 0.000 description 1
- PELIQFPESHBTMA-WLTAIBSBSA-N Thr-Tyr-Gly Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=C(O)C=C1 PELIQFPESHBTMA-WLTAIBSBSA-N 0.000 description 1
- LVRFMARKDGGZMX-IZPVPAKOSA-N Thr-Tyr-Thr Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)O)C(O)=O)CC1=CC=C(O)C=C1 LVRFMARKDGGZMX-IZPVPAKOSA-N 0.000 description 1
- KZTLZZQTJMCGIP-ZJDVBMNYSA-N Thr-Val-Thr Chemical compound [H]N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(O)=O KZTLZZQTJMCGIP-ZJDVBMNYSA-N 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- FEZASNVQLJQBHW-CABZTGNLSA-N Trp-Gly-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(O)=O)=CNC2=C1 FEZASNVQLJQBHW-CABZTGNLSA-N 0.000 description 1
- ZWZOCUWOXSDYFZ-CQDKDKBSSA-N Tyr-Ala-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 ZWZOCUWOXSDYFZ-CQDKDKBSSA-N 0.000 description 1
- NOXKHHXSHQFSGJ-FQPOAREZSA-N Tyr-Ala-Thr Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 NOXKHHXSHQFSGJ-FQPOAREZSA-N 0.000 description 1
- WTXQBCCKXIKKHB-JYJNAYRXSA-N Tyr-Arg-Arg Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O WTXQBCCKXIKKHB-JYJNAYRXSA-N 0.000 description 1
- IIJWXEUNETVJPV-IHRRRGAJSA-N Tyr-Arg-Ser Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CO)C(=O)O)N)O IIJWXEUNETVJPV-IHRRRGAJSA-N 0.000 description 1
- MBFJIHUHHCJBSN-AVGNSLFASA-N Tyr-Asn-Gln Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O MBFJIHUHHCJBSN-AVGNSLFASA-N 0.000 description 1
- CYDVHRFXDMDMGX-KKUMJFAQSA-N Tyr-Asn-His Chemical compound C1=CC(=CC=C1C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC2=CN=CN2)C(=O)O)N)O CYDVHRFXDMDMGX-KKUMJFAQSA-N 0.000 description 1
- XMNDQSYABVWZRK-BZSNNMDCSA-N Tyr-Asn-Phe Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC1=CC=CC=C1)C(O)=O XMNDQSYABVWZRK-BZSNNMDCSA-N 0.000 description 1
- QHEGAOPHISYNDF-XDTLVQLUSA-N Tyr-Gln-Ala Chemical compound C[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC1=CC=C(C=C1)O)N QHEGAOPHISYNDF-XDTLVQLUSA-N 0.000 description 1
- CKHQKYHIZCRTAP-SOUVJXGZSA-N Tyr-Gln-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O CKHQKYHIZCRTAP-SOUVJXGZSA-N 0.000 description 1
- LOOCQRRBKZTPKO-AVGNSLFASA-N Tyr-Glu-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 LOOCQRRBKZTPKO-AVGNSLFASA-N 0.000 description 1
- WVRUKYLYMFGKAN-IHRRRGAJSA-N Tyr-Glu-Glu Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 WVRUKYLYMFGKAN-IHRRRGAJSA-N 0.000 description 1
- SLCSPPCQWUHPPO-JYJNAYRXSA-N Tyr-Glu-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 SLCSPPCQWUHPPO-JYJNAYRXSA-N 0.000 description 1
- DZKFGCNKEVMXFA-JUKXBJQTSA-N Tyr-Ile-His Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1cnc[nH]1)C(O)=O DZKFGCNKEVMXFA-JUKXBJQTSA-N 0.000 description 1
- MVFQLSPDMMFCMW-KKUMJFAQSA-N Tyr-Leu-Asn Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O MVFQLSPDMMFCMW-KKUMJFAQSA-N 0.000 description 1
- QFXVAFIHVWXXBJ-AVGNSLFASA-N Tyr-Ser-Glu Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(O)=O QFXVAFIHVWXXBJ-AVGNSLFASA-N 0.000 description 1
- HRHYJNLMIJWGLF-BZSNNMDCSA-N Tyr-Ser-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=C(O)C=C1 HRHYJNLMIJWGLF-BZSNNMDCSA-N 0.000 description 1
- SYFHQHYTNCQCCN-MELADBBJSA-N Tyr-Ser-Pro Chemical compound C1C[C@@H](N(C1)C(=O)[C@H](CO)NC(=O)[C@H](CC2=CC=C(C=C2)O)N)C(=O)O SYFHQHYTNCQCCN-MELADBBJSA-N 0.000 description 1
- LUMQYLVYUIRHHU-YJRXYDGGSA-N Tyr-Ser-Thr Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(O)=O LUMQYLVYUIRHHU-YJRXYDGGSA-N 0.000 description 1
- WQOHKVRQDLNDIL-YJRXYDGGSA-N Tyr-Thr-Ser Chemical compound [H]N[C@@H](CC1=CC=C(O)C=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(O)=O WQOHKVRQDLNDIL-YJRXYDGGSA-N 0.000 description 1
- HMPMGPISLMLHSI-JBACZVJFSA-N Tyr-Trp-Gln Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](CC3=CC=C(C=C3)O)N HMPMGPISLMLHSI-JBACZVJFSA-N 0.000 description 1
- WYOBRXPIZVKNMF-IRXDYDNUSA-N Tyr-Tyr-Gly Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(O)=O)C1=CC=C(O)C=C1 WYOBRXPIZVKNMF-IRXDYDNUSA-N 0.000 description 1
- HZDQUVQEVVYDDA-ACRUOGEOSA-N Tyr-Tyr-Leu Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 HZDQUVQEVVYDDA-ACRUOGEOSA-N 0.000 description 1
- AEOFMCAKYIQQFY-YDHLFZDLSA-N Tyr-Val-Asn Chemical compound NC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 AEOFMCAKYIQQFY-YDHLFZDLSA-N 0.000 description 1
- NVJCMGGZHOJNBU-UFYCRDLUSA-N Tyr-Val-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)N NVJCMGGZHOJNBU-UFYCRDLUSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- UEOOXDLMQZBPFR-ZKWXMUAHSA-N Val-Ala-Asn Chemical compound C[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N UEOOXDLMQZBPFR-ZKWXMUAHSA-N 0.000 description 1
- IZFVRRYRMQFVGX-NRPADANISA-N Val-Ala-Gln Chemical compound C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)O)NC(=O)[C@H](C(C)C)N IZFVRRYRMQFVGX-NRPADANISA-N 0.000 description 1
- QGFPYRPIUXBYGR-YDHLFZDLSA-N Val-Asn-Phe Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)O)N QGFPYRPIUXBYGR-YDHLFZDLSA-N 0.000 description 1
- VLDMQVZZWDOKQF-AUTRQRHGSA-N Val-Glu-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N VLDMQVZZWDOKQF-AUTRQRHGSA-N 0.000 description 1
- BEGDZYNDCNEGJZ-XVKPBYJWSA-N Val-Gly-Gln Chemical compound CC(C)[C@H](N)C(=O)NCC(=O)N[C@H](C(O)=O)CCC(N)=O BEGDZYNDCNEGJZ-XVKPBYJWSA-N 0.000 description 1
- URIRWLJVWHYLET-ONGXEEELSA-N Val-Gly-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CNC(=O)[C@@H](N)C(C)C URIRWLJVWHYLET-ONGXEEELSA-N 0.000 description 1
- SYOMXKPPFZRELL-ONGXEEELSA-N Val-Gly-Lys Chemical compound CC(C)[C@@H](C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)O)N SYOMXKPPFZRELL-ONGXEEELSA-N 0.000 description 1
- UMPVMAYCLYMYGA-ONGXEEELSA-N Val-Leu-Gly Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O UMPVMAYCLYMYGA-ONGXEEELSA-N 0.000 description 1
- BTWMICVCQLKKNR-DCAQKATOSA-N Val-Leu-Ser Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C([O-])=O BTWMICVCQLKKNR-DCAQKATOSA-N 0.000 description 1
- HWNYVQMOLCYHEA-IHRRRGAJSA-N Val-Ser-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)N HWNYVQMOLCYHEA-IHRRRGAJSA-N 0.000 description 1
- OEVFFOBAXHBXKM-HSHDSVGOSA-N Val-Trp-Thr Chemical compound C[C@H]([C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](C(C)C)N)O OEVFFOBAXHBXKM-HSHDSVGOSA-N 0.000 description 1
- MIAZWUMFUURQNP-YDHLFZDLSA-N Val-Tyr-Asn Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H](CC(=O)N)C(=O)O)N MIAZWUMFUURQNP-YDHLFZDLSA-N 0.000 description 1
- JXWGBRRVTRAZQA-ULQDDVLXSA-N Val-Tyr-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CC=C(C=C1)O)NC(=O)[C@H](C(C)C)N JXWGBRRVTRAZQA-ULQDDVLXSA-N 0.000 description 1
- AEFJNECXZCODJM-UWVGGRQHSA-N Val-Val-Gly Chemical compound CC(C)[C@H]([NH3+])C(=O)N[C@@H](C(C)C)C(=O)NCC([O-])=O AEFJNECXZCODJM-UWVGGRQHSA-N 0.000 description 1
- AOILQMZPNLUXCM-AVGNSLFASA-N Val-Val-Lys Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCCN AOILQMZPNLUXCM-AVGNSLFASA-N 0.000 description 1
- 108010066342 Virus Receptors Proteins 0.000 description 1
- 102000018265 Virus Receptors Human genes 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 108010008685 alanyl-glutamyl-aspartic acid Proteins 0.000 description 1
- 108010041407 alanylaspartic acid Proteins 0.000 description 1
- KOSRFJWDECSPRO-UHFFFAOYSA-N alpha-L-glutamyl-L-glutamic acid Natural products OC(=O)CCC(N)C(=O)NC(CCC(O)=O)C(O)=O KOSRFJWDECSPRO-UHFFFAOYSA-N 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000009831 antigen interaction Effects 0.000 description 1
- 230000027645 antigenic variation Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 108010013835 arginine glutamate Proteins 0.000 description 1
- 108010093581 aspartyl-proline Proteins 0.000 description 1
- 108010068265 aspartyltyrosine Proteins 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 101150114014 cagA gene Proteins 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000003297 denaturating effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001378 electrochemiluminescence detection Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 108010063718 gamma-glutamylaspartic acid Proteins 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 244000000036 gastrointestinal pathogen Species 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 108010055341 glutamyl-glutamic acid Proteins 0.000 description 1
- 108010049041 glutamylalanine Proteins 0.000 description 1
- VPZXBVLAVMBEQI-UHFFFAOYSA-N glycyl-DL-alpha-alanine Natural products OC(=O)C(C)NC(=O)CN VPZXBVLAVMBEQI-UHFFFAOYSA-N 0.000 description 1
- 108010051307 glycyl-glycyl-proline Proteins 0.000 description 1
- 108010059898 glycyl-tyrosyl-lysine Proteins 0.000 description 1
- 108010081551 glycylphenylalanine Proteins 0.000 description 1
- 235000011868 grain product Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 108010040030 histidinoalanine Proteins 0.000 description 1
- 108010036413 histidylglycine Proteins 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 108010083708 leucyl-aspartyl-valine Proteins 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 108010005942 methionylglycine Proteins 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 108010024607 phenylalanylalanine Proteins 0.000 description 1
- 108010073101 phenylalanylleucine Proteins 0.000 description 1
- 108010051242 phenylalanylserine Proteins 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108010087846 prolyl-prolyl-glycine Proteins 0.000 description 1
- 108010053725 prolylvaline Proteins 0.000 description 1
- AAEVYOVXGOFMJO-UHFFFAOYSA-N prometryn Chemical compound CSC1=NC(NC(C)C)=NC(NC(C)C)=N1 AAEVYOVXGOFMJO-UHFFFAOYSA-N 0.000 description 1
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 238000013391 scatchard analysis Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000005100 tissue tropism Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 108010051110 tyrosyl-lysine Proteins 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/205—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Campylobacter (G)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
Abstract
A novel Helicobacter pylori blood group antigen binding (BAB) adhesin protein was isolated and purified, whereby said protein or fractions thereof bind specifically to fucosylated blood group antigens. The protein sequence of said adhesin is disclosed in this application. Simultaneously the DNA sequences for two genes, babA and babB, producing highly similar proteins, are disclosed. Said adhesin and/or DNA is useful for diagnose and therapy and/or prophylaxis directed against H. pylori induced infections, e.g. gastritis and acid peptic disease, i.e. active vaccination.
A new immunoglobulin composition, which exhibits specific activity to a Lewisb antigen binding Helicobacter pylori adhesin, or preferably, monoclonal and/or polyclonal antibodies to said adhesin offer a new and more efficient method of treatment and/or prevention of gastrointestinal diseases, caused by Helicobacter pylori or other Helicobacter species, i.e. passive vaccination.
Description
- The present invention relates to materials and methods for prevention, treatment and diagnosing of infections caused byHelicobacter pylori. More specifically the present invention relates to polypeptides and antibodies useful in vaccines for the treatment and prevention of pathologic infections caused by Helicobacter pylori strains. The present invention specifically relates to a bacterial blood group antigen binding adhesin (BAB-adhesin). The present invention further relates to polynucleotides useful for the recombinant production of said polypeptides and for use in immunisation therapies. In addition, it relates to polypeptides, antibodies, and polynucleotides used for the detection of said bacteria.
- The present invention further relates to new immunoglobulins, which exhibit specific activity to a blood group binding adhesin, expressed byHelicobacter pylori, methods for the production of said immunoglobulins, their isolation and use. The present invention further relates to the treatment and prevention of H. pylori induced infections in the gastrointestinal tract.
-
- Recent research has focused on the role ofHelicobacter pylori in the development of ulcers in the gastric mucosa. Recent findings show a strong connection between H. pylori and chronic, active gastritis and gastric ulcers. Furthermore, there appears to be a strong correlation between ventricular cancer and gastric ulcers. Traditional treatment of gastric ulcers has involved gastric resection, the administration of bismuth compositions, the administration of H2-blockers and the administration of pH-buffering agents, to mention a few examples.
- More recently, various forms of treatment have been supplemented with the administration of antibiotics. One problem with presently known treatments is the risk for treatment failure. Furthermore, not only do microbes develop antibiotic resistance, the antibiotics administered often upset the natural balance of benign microbes, colonising the intestinal tract. This leads to diarrhoea and other signs of intestinal discomfort, in addition to destabilising the benign flora in the intestines. Other treatments, e. g. H2-blockers often require life-long medication to prevent the recurrence of disease.
- The foregoing, together with the fact thatH. pylori is very widely spread among humans—according to a conservative estimate approximately 60% of all adult humans in the industrialised countries are infected—makes the diagnosing, prevention and treatment of H. pylori infections an urgent task.
- Further, the fact that developing countries frequently lack the resources for conventional treatment of gastric ulcers further underlines the importance of finding new ways of treatment and prevention ofH. pylori induced infections. It is obvious, for many reasons, that disease prevention with vaccines is a preferable mode. A vaccine would provide an easily administered and economical prophylactic regimen against H. pylori infections. An effective vaccine against H. pylori is nevertheless presently lacking.
-
- Attachment is essential for colonisation of the epithelial lining and bacteria express surface associated adhesion molecules that recognise specific carbohydrate or protein receptors on the cell surfaces or mucous lining. The specificity in this interaction in combination with the genetically regulated receptor distribution results in a restricted range of cell lineages and tissues available for colonisation. Several putative receptor structures have been described forH. pylori, such as the hemagglutinin-sialic acid, sulphated glycoconjugates and sulphatides. Recently, the fucosylated blood group antigens H-1 and Lewisb were described (Borén et al., Science, 262, 18921993), mediating specific adherence of H. pylori to human and rhesus monkey gastric surface mucous cells in situ. The H-1 and Lewisb antigens are part of the blood group antigens that define blood group O in the ABO system.
- Surface-exposed proteins are often constituents of the outer membrane. The outer membrane has a structural role and acts as a selective barrier, determining what enters the cell and what molecules are secreted. One class of outer membrane proteins are called porins, and create hydrophilic pores through the outer membrane where specific metabolites, such as sugar molecules, can cross. Recently the finding of a number of outer membrane proteins inH. pylori, was reported, which proteins were suggested to constitute a family of porin proteins.
- The BAB adhesin has previously been identified and shown to be localised on the bacterial surface ofH. pylori (SE 9602287-6). The blood group binding activity was shown to be pH dependent and the present inventors present evidence that the binding affinity to the Lewisb receptor reveals a high equilibrium constant. For the purification of the BAB adhesin, a crosslinker-labelled receptor conjugate was used in order to mediate specific transfer of biotin to the adhesins on the bacterial surface. Thereafter the biotin-labelled adhesin could be extracted by streptavidin coated magnetic beads. Determination of the amino terminal amino acid sequence of the purified BAB adhesin exhibit homologies to outer membrane proteins of H. pylori porins.
- Intensive research has been directed to the immunological treatment and prevention ofH. pylori induced infections.
EP 0 484 148 (Ando & Nakamura) describes a method for treating and/or preventing upper gastrointestinal disease in mammals, said method comprising orally administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising anti-Helicobacter pylori polyclonal immunoglobulins and a pharmaceutically acceptable carrier. Said description further dwells on the combination of said treatment in combination with the administration of antibiotics. As the method of producing said polyclonal antibodies,EP 0 484 148 describes the isolation and purification of anti-H. pylori immunoglobulins from the sera and milk of mammals. H. pylori itself was not found in the stomachs of cows, goats, sheep, swine or horses, according toEP 0 484 148, but it was assumed that these animal species have colonizing microorganisms with antigenic determinants similar to those of H. pylori because they have immunoglobulins which cross-react to strains of H. pylori found in humans. Preferably, according toEP 0 484 148, large mammals, e.g. pregnant cows, are immunized with whole cells of H. pylori and the immunoglobulins subsequently extracted from the milk or colostrum. In the immunization experiments, NCTC Strain 11362 and clinical isolate H. pylori No. 153 were used to trigger the production of immunoglobulins. On the other hand, NCTC Strain 11637 was used for analysing purposes. Immunization is claimed to yield an anti-H. pylori titer in the milk of such magnitude, that daily doses of 0.01-0.1 g/day immunoglobulin composition, are sufficient for successful therapy. The claimed interval of 0.01-0.1 g/day is however not supported by the experiments presented by Ando & Nakamura and so low doses have hitherto not proven efficient in clinical tests. The doses actually used in example 5 and 7 are in the order of magnitude of 1 g/day, i.e. 10-fold the upper limit of the given interval. Furthermore, it is very unlikely, that unspecific immunoglobulin mixtures as those manufactured by Ando & Nakamura, would be effective in claimed doses as similar doses are ineffective against other gastrointestinal pathogens. The simultaneous administration of antibiotics, extensively discussed in the description, underlines the insufficiency of the disclosed immunoglobulins. -
EP 0 469 359 (Cordle & Schaller) likewise describes the immunization of mammals, preferably pregnant cows, with formalin killed H. pylori bacteria (ATCC Strain 26695). Anti-H. pylori polyclonal antibodies were isolated and purified from the milk and finally fed to piglets, in amounts of about 0.5 g immunoglobulins, three times daily. The results were assessed by determination of the number of biopsy specimens, which were positive for Gram-negative bacteria after the trial. Gram-negative bacteria was found in 78% of the piglets fed a non-immune nutrient but only (Sic!) in 35% of the piglets fed a nutrient containing so called specific anti-H. pylori antibodies. - Anti-H. pylori polyclonal antibodies, effective to cause aggregation of H. pylori, have thus been administered orally as a regimen in the treatment and prevention of H. pylori induced infections in the gastrointestinal tract. Nevertheless, as also noted in
EP 0 484 148 A1, it is still not clear, how many antigenic determinants are present on the surface of H. pylori. The occurrence of a wide variety of H. pylori strains, makes questionable the practical efficiency of any polyclonal immunological therapy according to the state of the art. Immunization using whole bacteria will always trigger a highly polyclonal immunresponse with a low level of antibodies against a given antigenic determinant. This is underlined e.g. by the results presented by Cordle & Schaller, where, although the number of Helicobacter positive biopsies were reduced, complete cure was not obtained through the treatment according to their invention. - It is notable, that the dose of immunoglobulin needed for oral prophylaxis or therapy has not yet been clearly defined. In a normal human adult, approximately 5 g IgA is produced and secreted at mucosal surfaces each day. Obviously, doses of this magnitude are economically and practically unfeasible for large-scale therapy or prophylaxis. In studies on the effect of oral immunoglobulin on rotavirus infection, daily doses in the interval of 600 to 9000 mg have been tried in clinical tests. Successful intervention has also been reported when treatingH. pylori and cryptosporidial infections with daily administrations of 3 to 15 g immunoglobulin from immunized cows (Hammarström et al., Immunol Rev, 139 (1994) 43-70). Generally speaking, all studies hitherto point to the necessity of using high doses of immunoglobulins when trying to combat an ongoing infection. The need for more specific immunoglobuline preparations, allowing the use of smaller doses, is thus an urgent one.
- To maximize the potency of an immunological regimen for the treatment and prevention ofH. pylori, it is of great importance to find a specific conserved antigenic determinant, which plays a central role for the pathogenicity of H. pylori. Using such an antigenic determinant would make it possible to produce highly specific and therapeutically efficient novel polyclonal and/or monoclonal immunoglobulin preparations.
- The above problem of providing specific, cost-efficient and therapeutically superior immunoglobulin preparations for the treatment and prevention ofH. pylori has now been solved through the composition and methods according to the attached patent claims. The present inventors have now surprisingly shown, that highly specific and therapeutically efficient polyclonal and/or monoclonal immunoglobulin preparations can be provided through the immunization of an animal with an adhesin protein, specific for H. pylori. Said adhesin protein is characterized already in the priority applications SE 9602287-6 and SE 9701014-4, which hereby are referred to in their entirety. The invention will now be described in closer detail with reference to the attached, non-limiting figures and examples.
- One objective of the present invention was to further purify and characterize theH. pylori blood group antigen binding (BAB) adhesin to make possible the development of methods and materials for specific and selective diagnosing and treatment of H. pylori induced infections and related diseases and the development of said methods and materials. A further and equally important objective was to determine the DNA sequences of the genes involved in the expression of this protein. These objectives were fulfilled through the protein specified in
claim 1, the DNA disclosed in claim 13 and 14 and the methods and materials specified in the subsequent claims. The DNA sequences are attached asAppendix Appendix 3. - FIG. 1A) illustrates the bacterial binding to soluble blood group antigens.H. pylori strains were incubated with 125I-labeled blood group antigen glycoconjugates and bound 125I-activity was measured (Note the absence of blood group antigen binding shown for strains MO19 and 26695.),
- FIG. 1B) illustrates an receptor displacement assay.
Strain CCUG 17875 was first incubated with 10 ng 125I-labeled Leb antigen glycoconjugate and the complex was then challenged (1 h) with an excess of unlabeled Leb or Lea glycoconjugate, before the 125I-activity in the bacterial pellet was measured. Concentrations of the unlabeled glycoconjugate ranged from 50 ng to 8 μg and C) shows the results of a Scatchard analysis of the H. pylori-Leb antigen interaction. Bacterial binding to the Leb glycoconjugate was titrated to an affinity constant (Ka) value of 8×10−10 M−1 (13). - FIG. 2: Upper panel: Prevalence of the BabA adhesin in the bacterial population. Cells of
strain CCUG 17875 were incubated with biotinylated Leb (A) or Leb (B) glycoconjugate. Bound biotinylated Lewis-conjugate was detected with FITC-labeled streptavidin (green fluorescence) and bacteria were counterstained with propidium iodine (red fluorescence). Lower panel: Localisation of the BabA adhesin. For electron microscopy (15) cells ofstrain CCUG 17875 were incubated with biotinylated Leb (C) or Lea (D). - FIG. 3 shows the characterization of the molecular weight of the BabA adhesin by the use of receptor overlay analysis (A, B) and receptor activity directed affinity tagging of BabA (C).
- FIG. 4 shows receptor activity directed affinity tagging and protein purification of the BabA adhesin.
- FIG. 5 shows the translated amino acid sequences for the babA and babB genes, corresponding to the N-terminal domain of the BabA adhesin.
- FIG. 6 shows the procentual inhibition ofH. pylori binding to 125I-labeled Lewis b antigen for different preparations as a function of the antibody titre.
- FIG. 7 shows a Western blot detection of the BabA adhesin by the different antibody preparations.
- FIG. 8 shows four Western blot analyses ofH. pylori proteins by the different antibody preparations.
- The blood group antigen binding adhesin, BabA, has now been biochemically characterized and purified by a novel technique, receptor Activity Directed Affinity Tagging (Retagging). Two genes, babA and babB were found to code for two different but very similar proteins. The present invention thus comprises a novel blood group antigen binding adhesin according to
claim 1 and the subsequent claims. The DNA sequences are disclosed in appendices 1 (babA) and 2 (babB). The protein sequences is disclosed inappendix 3. The invention also includes any pharmaceutical composition comprising said adhesin protein and/or fractions thereof. Examples of such pharmaceutical compositions are for example medicaments for the prevention or treatment of Helicobacter pylori induced gastritis, gastric and duodenal ulcers and gastric adenocarcinoma. Optionally said pharmaceutical composition additionally encompasses pharmaceutically acceptable excipients. - Further, the present invention comprises the BAB-adhesin gene or genes for expression of an adhesin protein according to the invention. Said invention also comprises a novel method for the isolation and purification of said adhesin. The disclosed genes are contemplated to function as a cassette system, the organism alternating between these to avoid immunity in the host. It is very likely, that homologies of the disclosed sequences exist and additionally supplement said cassette function in other strains ofH. pylori. Also, genes corresponding to a homology of the first 40 amino acids or genes, corresponding to a homology of the last, about 300 amino acids, can function to this effect. It is further highly likely, that Helicobacter pylori is able to switch between several genes, similar to the disclosed genes, in a so-called cassette system.
- The invention additionally comprises monospecific antisera produced using the novel adhesin protein and/or fractions thereof. Said monospecific antisera is preferably produced according to any suitable, conventional method for producing monospecific antisera in vitro or in vivo, e.g. by inoculating a suitable animal. Such methods are familiar to a person skilled in the art. Antibodies raised in a suitable animal or in the patient to be treated, can subsequently be administered locally, e.g. orally to the patient.
- The invention further comprises the use of said monospecific antisera for the manufacturing of a test kit for quantitative or qualitative determinations of adhesin protein or fractions thereof in cells, tissues or body fluids.
- The invention further comprises the use of said adhesin protein or corresponding DNA for use in therapy or immunisation and/or in the manufacture of compositions for said uses. The invention specifically encompasses the use of said DNA for immunisation therapy and for the manufacture for compositions for such therapy. Preferably, in an immunisation therapy where said composition is administered orally to a patient, the adhesin protein, fractions thereof or said DNA is administered in combination with a pharmaceutically suitable immunostimulating agent. Examples of such agents include, but are not limited to the following: cholera toxin and/or derivatives thereof, heat labile toxins, such asE. coli toxin and similar agents. The composition according to the present invention can further include conventional and pharmaceutically acceptable adjuvants, familiar to a person skilled in the art of immunisation therapy. Preferably, in an immunisation therapy using the inventive DNA or fractions thereof, said DNA is preferably administered intramuscularly, whereby said DNA is incorporated in suitable plasmide carriers. An additional gene or genes encoding a suitable immunostimulating agent can preferably be incorporated in the same plasmide.
- Said immunisation therapies are not restricted to the above-described routes of administration, but can naturally be adapted to any one of the following routes of administration: oral, nasal, subcutaneous and intramuscular. Especially the oral and nasal methods of administration are promising, in particular for large-scale immunisations.
- The present inventors have surprisingly shown, that highly specific and therapeutically efficient polyclonal and/or monoclonal immunoglobulin preparations can be provided through the immunisation of an animal with an adhesin protein or fractions thereof, specific forH. pylori. When considering immunisation against H. pylori, it is worth noting that the infection is known to be lifelong despite a vigorous immune response in the gastric mucosa. An increased local production of IgA in the mucosa is not necessarily enough and the administration of monospecific antibodies directed against a central virulens factor, such as the adhesin according to the present invention, may constitute a more effective approach.
- The term “immunisation” refers here to a method for inducing a continous high level of antibody and/or cellular immunresponse. The term “animal” here preferentially denotes any member of the subphylum Vertebrata, a division that includes all animals, including mammals, which are characterized by a segemented bony or cartilaginous spinal column. All vertebrates have a functional immune system and respond to antigens by producing antibodies. The term “protein” is used here to denote a naturally occurring polypeptide and the term “polypeptide” is used here in its widest meaning, i.e. any amino acid polymer (dipeptide or longer) linked through peptide bonds. Accordingly the term “polypeptide” comprises proteins, oligopeptides, protein fragments, analogues, muteins, fusion proteins and the like. The term “antibody” as used in this context includes an antibody belonging to any of the immunological classes, such as immunoglobulins A, D, E, G or M. Of particular interest are nevertheless immunoglobulin A (IgA) since this is the principle immunoglobulin produced by the secretory system of warm-blooded animals. However, in cow colostrum, the main antibody class is
IgG 1. - Borén et al. have recently isolated and characterized a Lewisb binding protein with a molecular weight of about 73500 Da (See the priority applications SE 9602287-6 and SE 9701014-4, which are referred to in their entirety). This adhesin protein is thought to be a conserved structure and specific for pathogenic strains of H. pylori. Said protein is specific for at least one of the H. pylori strains included in the following group:
CCUG 17875, NCTC 11637, A5, P466, G109, G56, Ba 185, Ba 99, 931 and 932. - This adhesin protein or immunologically effective fractions thereof are characterized in that the following amino acid sequence is included:
- EDDGFYTSVGYQIGEAAQMV
- or homologues thereof.
- The following DNA sequence or homologues thereof is included in DNA for expression of said adhesin protein or fractions thereof:
5′-GAAGACGACGGCTTTTACACAAGCGTAGGCTATCAAATCGGTGAAGCCGCTCAAATGGTA-3′ - According to one embodiment of the invention, a pregnant mammal, preferably a cow or another suitable domestic animal, is immunised with said Lewisb binding adhesin protein or fractions thereof. The adhesin protein or fractions thereof is/are preferably injected intramuscularly or subcutaneously in the chosen animal, optionally together with suitable adjuvants. Examples of such adjuvants include, but are not limited to immunostimulating agents such as cholera toxin and/or derivatives thereof, heat labile toxins, such as E. coli toxin and similar, conventional agents, such as classical adjuvants including mineral and vegetable oils. Subsequent to the regimen of immunization, comprising a necessary amount of doses, including so called booster-doses, over a time span allowing for optimal immunoglobulin expression, milk or sera is collected from said animal. Preferably the cow colostrum, which is specially high in immunoglobulins, is collected. The specific immunoglobulin fraction according to the present invention is then separated and purified in a conventional manner, e g including separation of fats, protein precipitation and concentration by ultrafiltration.
- According to another embodiment of the invention, a bird, preferably a chicken or another suitable domestic bird, is immunized with said Lewisb binding adhesin protein or fractions thereof. The adhesin protein or fractions thereof is preferably injected intramuscularly or subcutaneously in the chosen bird, optionally together with suitable adjuvants. Examples of such adjuvants include, but are not limited to immunostimulating agents such as cholera toxin and/or derivatives thereof, heat labile toxins, such as E. coli toxin and similar, conventional agents, such as classical adjuvants including mineral and vegetable oils. Subsequent to the regimen of immunization, comprising a necessary amount of doses, including so called booster-doses, over a time span allowing for optimal immunoglobulin expression, sera or eggs is/are collected from said animal. Preferably the egg yolk, which is specially high in immunoglobulins, is collected. The specific immunoglobulin fraction according to the present invention is then separated and purified in a conventional manner, e g including protein precipitation and ultrafiltration. Alternatively, the egg yolk being of high nutritional value in addition to containing a high titer of specific antibodies according to the present invention, can be administered as such.
- According to a preferred embodiment of the present invention, monoclonal immunoglobulin is produced by establishing transgenic animals. Said transgenic animals can be chosen from the following group of species: mammals, e.g. cow, goat and rabbit, and birds: e.g. chicken, duck, turkey. The mammal most preferably used is cow and the most preferable bird is chicken. Further developments of transgenic animals such as mice and rats could also offer new possibilities. The choice of animal is naturally governed by availability and local adaptation.
- According to one embodiment, a stock of transgenic animals according to the present invention, adapted to the local conditions, are kept locally, e.g. in villages in developing countries to function as local units for the production of immunoglobulins for oral administration. For example transgenic cows, goats or chicken are suitable for this purpose and preferably chicken are used. Consumption of the milk or preferably the eggs, produced by the transgenic animals, can help to eradicate presently very difficult infectious diseases, e.g. diseases caused byH. pylori.
- According to yet another embodiment of the present invention, monoclonal antibodies can be produced using the hybridoma method. The hybridoma method is well known to a skilled worker in the field of biochemistry and it is described e. g. in Galfre, G. And Milstein, C., Preparation of monoclonal antibodies: strategies and procedures (Methods in Enzymology, 73:3-46, 1981). A suitable host animal is immunized with the Lewisb binding adhesin protein or fractions thereof. When the immunization is accomplished, the animal is sacrificed, spleen cells collected and fused with cells from a neoplastic cell line, preferably myeloma cells. By choosing the growth conditions, the successfully fused hybridoma cells can be selected. The monoclonal antibodies produced by the hybridoma cell line can then be administered orally in a regimen for treatment and/or prevention of H. pylori infections.
- Preferably the polyclonal and/or monoclonal antibodies are purified prior to administration and, more preferably, admixed with pharmaceutically suitable carriers and/or adjuvants. Examples of suitable carriers are saline, pharmaceutically acceptable fats, oils, carbohydrates and proteins. The carrier or carriers is/are preferably chosen so that the solubility and absorption of the immunoglobulin in the mucus layer lining the stomach is enhanced. Using suitable adjuvants the stability, therapeutic efficiency and nutritional value of the composition can be improved. To improve stability under storage, the immunoglobulin composition can be lyophilized. Regardless of the exact preparation and formulation, it is of central importance to avoid denaturating the immunoglobulins.
- The higher specificity, exhibited by the immunoglobulin preparation of polyclonal and/or monoclonal antibodies according to the invention, makes it possible use substantially lower doses compared to those presently used, thus lowering the cost and improving the availability of the treatment. The use of specific, monoclonal antibodies can make it possible to further lower the doses. The doses are in all cases a function of the antibody titer of the preparation. A high titer naturally allows the use of lower doses.
- According to one embodiment of the invention, an immunoglobulin preparation is manufactured as follows: an animal is immunized with a Lewisb binding adhesin protein or fractions thereof, expressed by Helicobacter pylori, the immunoglobulin fraction is isolated from a excretion of said animal and subsequently purified. The purified immunoglobulin composition is admixed with suitable carriers and adjuvants to form a immunoglobulin preparation for the prevention or treatment of H. pylori infections. In cases where the antibody titer is sufficiently high and the other constituents of the immunoglobulin composition isolated from the animal are harmless, for example in the case of colostrum from immunized cows or egg yolk from immunized chicken, there is always the option of administering the colostrum or egg yolk to the patient without any further treatment of the colostrum or egg yolk.
- The immunoglobulin composition according to the invention is preferably administered orally to the patient, in the smallest therapeutically or prophylactically effective dose. Presently conceived are doses in the interval of 0.1 to 1000 mg/day, preferably in the interval of 0.1 to 100 mg/day. The chosen doses naturally depend on the antibody titer of the preparation in question. The exact doses and the regimen of administration can be chosen by the physician responsible for the patient, infected byHelicobacter pylori. Routine experimentation and later, with increasing experience of this method, empirical information will suffice to establish the required amount. Multiple dosages may be used, as needed, to provide the desired level of therapeutic or profylactic effect. The immunoglobulin preparations according to the present invention can also, being free from adverse side effects and imposing practically no danger of overdosing, be taken prophylactically or therapeutically by a person without medical supervision.
- A therapeutical effect can be attained, except with the specific antibody according to the present invention, also with at least two Fab-fragments of said antibody. Said embodiment is also encompassed by the scope of the present invention.
- According to yet another embodiment, avirulent microorganisms, preferably bacteria, are used as expression systems for the specific antibody according to the present invention. An “avirulent microorganism” in this context is a microorganism which has the ability to colonize and replicate in an infected individual, but which does not cause disease symptoms associated with virulent strains of the same species of microorganism. The definition inherent in the GRAS (Generally Regarded As Safe) concept can be applied here. A GRAS-organism is suitable for use according to the present invention, provided that the organism externalises the antibody or can be modified to this effect The term “microorganism” as used herein includes bacteria, protozoa and unicellular fungi. Preferably, bacteria are used as expression systems, e.g. bacteria of the genusLactobacillus, Streptococcus or Enterobacteriae. The above mentioned expression system can be utilised in vitro for the production of the specific antibody according to the present invention or, according to a further embodiment of the invention, the micro-organism constituting the expression system can be administered directly to the patient. The micro-organisms can be harvested and administered as such, but they are preferably mixed with a suitable carrier, mixed in a suitable foodstuff, lyophilised, encapsulated or treated in any other conventional way, used for the delivery of viable micro-organisms to the gastrointestinal tract.
- According to yet another embodiment, avirulent microorganisms, preferably bacteria, are used as expression systems for the specific adhesin protein according to the present invention. An “avirulent microorganism” in this context is a microorganism which has the ability to colonize and replicate in an infected individual, but which does not cause disease symptoms associated with virulent strains of the same species of microorganism. The definition inherent in the GRAS (Generally Regarded As Safe) concept can be applied here. A GRAS-organism is suitable for use according to the present invention, provided that the organism externalises the adhesin protein or can be modified to this effect. The term “microorganism” as used herein includes bacteria, protozoa and unicellular fungi. Preferably, bacteria are used as expression systems, e.g. bacteria of the genusLactobacillus, Streptococcus or Enterobacteriae. The above mentioned expression system can be utilised in vitro for the production of the specific adhesin according to the present invention or, according to a further embodiment of the invention, the micro-organism constituting the expression system can be administered directly to the patient. The microorganisms can be harvested and administered as such, but they are preferably mixed with a suitable carrier, mixed in a suitable foodstuff, lyophilised, encapsulated or treated in any other conventional way, used for the delivery of viable micro-organisms to the gastrointestinal tract.
- The exact doses and the regimen of administration of said micro-organisms can be chosen by the physician responsible for the patient, infected byHelicobacter pylori. Routine experimentation and later, with increasing experience of this method, empirical information will suffice to establish the required amount. Multiple dosages may be used, as needed, to provide the desired level of therapeutic or prophylactic effect. The avirluent micro-organism expressing the antibody or adhesin protein according to the present invention can also, being free from adverse side effects and imposing practically no danger of overdosing, be taken prophylactically or therapeutically by a person without medical supervision. A preferred carrier in this specific application is a foodstuff, e.g. a fermented product such as fermented cereal or dairy product.
- The creation of previously mentioned expression systems and still earlier mentioned methods of creating hybridomas and transgenic animals can include steps involving recombinant DNA techniques. Recombinant DNA techniques are now sufficiently well known and widespread so as to be considered routine. In very general and broad terms, recombinant DNA techniques consist of transferring part of the genetic material of one organism into a second organism, so that the transferred genetic material becomes a permanent part of the genetic material of the organism to which it is transferred. Methods for achieving this are well known and the mere choice of specific methods for achieving the objectives, set out in the present description and claims, fall under the scope of the invention.
- It is possible, thatH. pylori alone or together with related slow-acting bacteria are involved in the genesis and aggravation of other chronic inflammatory diseases in the gastrointestinal tract. It is obvious for a skilled practitioner how to modify the present invention, within the scope of the claims, to gain utility in the treatment and/or prevention of such diseases. Examples of such diseases are ulcerative colitis, Crohn's disease, sarcoidosis, Wegener's granulomatosis and other vasculithic disorders, as well as various neoplasms, including carcinomas of the colon, pancreas and prostate.
-
CCUG 17875 was obtained from CCUG, Göteborg, Sweden. Strain A5, a gastric ulcer isolate, from Astra Arcus, Södertälje, Sweden. Strains P466 and MO19 were described previously (Borén et. al, Science, 262, 1892(1993)).Strain 26695 came from Dr. K. A. Eaton, The Ohio State University and its genome was recently sequenced by TIGR, Rockville, Md., USA. The panel of 45 H. pylori clinical isolates came from the University Hospital in Uppsala, Sweden. Bacteria were grown at 37° C. in 10% CO2 and 5% O2 for 48 h. - All blood group antigen glycoconjugates used, i.e. semi-synthetic glycoproteins constructed by the conjugation of purified fucosylated oligosacharides to serum albumin were from IsoSep AB, Tullinge, Sweden. The RIA was performed according to Falk et al. (Meth. Enzymol., 236, 353, 1994) with some modifications; the H-1, Leb, Lea, H-2, Lex and Ley glycoconjugates were 125I-labeled by the Chloramine T method. 1 ml of bacteria (A600=OD 0.10) was incubated with 300 ng of 125I-labelled conjugate (i.e. an excess of receptors) for 30 min. in phosphate buffered saline (PBS), 0.5% albumin, 0.05% Tween-20 (BB-buffer). After centrifugation, 125I-activity in the bacterial pellet was measured by gamma scintillation counting.
- In this study the present inventors' first biochemically characterized and identified theH. pylori blood group antigen binding adhesin, BabA. H. pylori strains were analysed for binding to soluble 125I-labeled fucosylated blood group antigens (FIG. 1A). Binding of these strains to the soluble blood group antigens correlate with adherence in situ. The prevalence of blood group antigen binding (BAB)-activity was assessed among 45 clinical H. pylori isolates and the majority of the isolates, 71%, express Leb antigen binding properties (data not shown). In contrast, none of the reference strains (FIG. 1A), or strains from the panel of 45 clinical isolates, bind to the Lea, H-2, Lex, or Ley antigens. These results support our previous findings of high receptor specificity for the Leb and H-1 blood group antigens and demonstrate the high prevalence of BAB activity among clinical isolates.
- Based on the presence or absence of virulence factors such as the Cytotoxin associated gene A (CagA) and the Vacuolating cytotoxin A (VacA),H. pylori strains are classified as type I or type II strains. H. pylori isolates from patients with duodenal ulcers most often express the VacA and the CagA-proteins, i.e. type-I strains. By definition, type II strains express neither markers. Twenty-one clinical isolates previously defined for expression of CagA and VacA were analysed for Leb antigen binding properties. Expression of CagA was found to correlate with bacterial binding to the Leb antigen (Table 1). The cagA gene belongs to a 40 kb pathogenicity island that encodes components of secretion and transport systems. These findings could indicate functional crosstalk between the cag pathogenicity island and the BabA adhesin gene, for the correct presentation of the BabA adhesin protein in the bacterial outer membrane.
- To further characterize BabA, the present inventors determined the affinity constant (Ka) between BabA and the Leb antigen. Since Ka-values are based on equilibrium conditions (13), the present inventors first analysed the interaction by performing receptor displacement analysis. H. pylori CCUG 17875 (positive for Leb binding, FIG. 1A) was first incubated with 125I-labeled Leb glycoconjugate. Then unlabeled Leb glycoconjugate was added in a dilution series. The unlabeled Leb conjugate displaced the bound 125I-labeled Leb glycoconjugate efficiently (FIG. 1B). The results demonstrate that the receptor-adhesin complex formed is in a true state of equilibrium. An equivalent excess of Lea glycoconjugate did not dissociate the Leb-BabA complex, verifying the high receptor specificity (FIG. 1B). The Ka-value for the Leb-BabA complex of
strain CCUG 17875 was titrated with Leb glycoconjugate in concentrations from 10 ng to 260 ng/ml and determined to be of an high affinity close to 1×1010M−1(FIG. 1C). The number of Leb glycoconjugate molecules bound to BabA on the bacterial cell surface was calculated to be around 500 per cell. This number is similar to the number or fimbriae organelles on the surface of E. coli (14). However, for the BabA adhesin, the calculations are based on the assumption that the majority of bacterial cells in the experiment exhibit an equal number of adhesin molecules with Leb antigen binding properties.TABLE 1 BAB activity among H. pylori Type I and Type II strains Type Strain BAB activity Type I CCUG 17874 − CagA+, VacA+ G39 − G11 − G20 − G27 + G56 + G106 − G109 + 932 + Ba185 + 87A300 + Type Ia 931 + CagA+, VacA+ Ba99 + Ba179 + Ba194 + Type Ib G12 − CagA−, VacA+ Type Id G104 − ΔcagA, VacA+ Tx30 − Type II G21 − CagA−, VacA− G50 − G198 − - To determine the prevalence of BabA in the bacterial population, strain
CCUG 17875 was incubated with Leb or Lea antigens, and bacterial binding activity was visualised by confocal fluorescence microscopy (FIG. 2, upper panel). The analyses demonstrate the high prevalence of BabA binding activity in the bacterial population to the Leb antigen (FIG. 2A, green staining) and the complete lack of binding to the Lea antigen (FIG. 2B, red counter staining). - Next, the localisation and density of BabA on the bacterial cell surfaces was investigated by immunogold electron microscopy. The Leb antigen binding activity of the adhesin localised gold particles to the bacterial outer membrane (FIG. 2C). Individual bacterial cells exhibit an equal number of gold particles (data not shown). When the Leb antigen was substituted with the Lea antigen (lacking receptor activity), no gold particles were detected (FIG. 2D).
- The molecular weight of BabA was characterized by receptor overlay analysis. A protein extract of
strain CCUG 17875 was separated on SDS-PAGE and blotted to a membrane. The membrane was incubated with biotinylated Leb glycoconjugate, followed by detection with streptavidin and enhanced chemiluminescence. The BabA adhesin activity corresponds to a single 74 kDa band (FIG. 3A). The 40 kDa band is presumably endogenous peroxidase activity since it stains independently of the Leb conjugate overlay (lane 3). BabA was very heat stable and could regain some activity after heating to 97° C. (FIG. 3A, lane 2). The panel of strains exhibited the same molecular weight of BabA (FIG. 3B). - To purify BabA, a novel technique was developed, Receptor Activity Directed Affinity Tagging (ReTagging). Multi-functional crosslinking agents with radiolabeled donating tags have been previously used for receptor-ligand characterization studies. However, the use of affinity donating tags, such as biotin residues presented on flexible spacer structures, adds a new dimension to the applicability of crosslinker technology. An affinity tag, biotin, is transferred to the adhesin protein by the receptor activity and is used for further identification and for affinity purification of the adhesin part of the interaction, by streptavidin (FIG. 4A, B).
- A multi-functional crosslinking agent with a biotin donating handle was attached to the Leb glycoconjugate. The receptor activity of the Leb glycoconjugate subsequently directed the targeted biotin tagging of the BabA adhesin protein (FIG. 4A, B). After crosslinking, the bacterial protein from strains A5, P466, and
CCUG 17875 were separated on SDS-PAGE. Immunodetection with streptavidin demonstrated a biotin tagged protein, with the molecular weight of 74 kDa (FIG. 3C) (28), These results support the estimates of the molecular weight from the previous overlay analyses (FIG. 3B). Strain MO19 devoid of Leb antigen binding properties (FIG. 3B) (FIG. 1A), was negative for binding also in this set of analyses (FIG. 3C). - The high specificity in the ReTagging technique provided a method for purification of the adhesin protein. Strains
CCUG 17875 and A5, that both express the BabA adhesin (FIG. 1A) were processed by the ReTagging technique using crosslinker labelled Leb receptor conjugate as the biotin donor. After crosslinking, bacteria were suspended in SDS sample buffer. Streptavidin coated magnetic beads were subsequently added to the solubilised proteins, and biotin tagged BabA was extracted (FIG. 4C). The N-terminal 20 amino acid sequences of the BabA adhesins from strains CCUG 17875 (Australia) and A5 (Sweden) were found to be identical, indicating a biologically conserved protein (FIG. 5). Recently, a series of outer membrane proteins from H. pylori were characterized. These proteins, HopA-E, are homologous in their N-terminal sequences to BabA (17), possible indicating a motif for a common secretion mechanism. The biotin tagged BabA adhesin was purified more than 3000-fold from the cell extract, and the yield was calculated to 20%. However, based on data from the Scatchard plots, the level of available BabA adhesin would be about 5-times higher, i.e. approximately 1 mg adhesin/750 mg bacterial protein, which nevertheless could be the reason for the high signal to noise ratio (FIG. 3B). The purification of BabA via the ReTagging technique indicates the potential of this technique for the purification of lectins in complex receptor-ligand interactions, such as the selectin family of cell adhesion molecules. - To clone the gene encoding BabA, the N-terminal 20 aa sequence was utilised for the construction of degenerate primers (18). Two sets of clones were identified which both encode two different but very similar proteins. Both genes code for proteins having almost identical N-terminal domains and identical C-terminal domains, complicating the identification of the functional BabA gene. (FIG. 5). To identify the corresponding gene, the BabA adhesin was purified in large scale by ReTagging. This provided enough protein for an extended amino terminal sequence. 41 amino acids were identified and these residues unambiguously discriminated between the two genes by the differences in aa-
positions - Immunisation experiments with adhesins fromBordetella pertussis (21) indicate the potential for outer membrane proteins to act as vaccine candidates (discussed in ref. 22). In a mouse model for persistent H. pylori infection, oral immunisation with H. pylori antigens proved protective against H. pylori infection (10). However, results from animal models are difficult to evaluate for human specific pathogens, such as H. pylori and Polio virus. For Polio, an animal model has been achieved by expressing the virus receptor in transgenic nice (23). A similar strategy was taken for H. pylori. A transgenic mouse was constructed by the use of an al,¾-fucosyltransferase, driving the synthesis of the human specific Leb antigen in the gastrointestinal tract (24). The Lewis b mouse can be useful for the evaluation of the role of the BabA adhesin as a colonisation/virulence factor and in addition for the evaluation of BabA as a vaccine candidate against acid peptic disease and gastric adenocarcinoma.
- In the present study the ReTagging technique was used for the purification of the adhesin part of the microbial receptor-ligand interaction. By the use of purified adhesin/lectin-protein, the ReTagging technique could, in addition, be used to further study the receptor part of the interaction. Identification of the biologically active receptor structure, carrying Leb oligosaccharides, would aid in the understanding of the mechanisms supporting the chronic H. pylori infection.
- Inhibition ofH. pylori binding to 125I-labeled Lewis b antigen by preparations is presented graphically, as a function of antibody concentration (mg/ml) in FIG. 6: 1 ml aliquots of H. pylori bacteria (A600=OD 0.10) were pre-incubated with dilution series of antibody preparations, in 0.01-10 mg/ml for 2 hours in phosphate buffered saline (PBS), 0.5% albumin, 0.05% Tween-20. Then 500 ng of 125I-labeled conjugate (i.e. an excess of receptor structure) was added and incubated for 30 minutes. After centrifugation, 125I-activity in the bacterial pellet was measured by gamma scintillation counting. The Lewis b blood group antigen glycoconjugates used, i.e. semi-synthetic glycoproteins constructed by the conjugation of purified fucosylated oligosaccharides to serum albumin were from IsoSep AB, Tullinge, Sweden.
- Western blot detection of the BabA adhesin by the different antibody preparations is presented in FIG. 7: Molecular weight rainbow marker (2 μL) from Amersham, Buckinghamshire, England, was dissolved in SDS sample buffer (lane 1). Approx. 100 ng of purified BabA adhesin (approx. 74 kDa with degradation product of approx. 55 kDa) was dissolved in SDS sample buffer (lane 2). SDS solubilized protein extracts of
strain CCUG 17875 were prepared by dissolving the bacterial pellet corresponding to 0.15 ml of bacteria (A600=OD 0.10) by SDS sample buffer (lane 3). The 3 protein samples were then boiled at 100° C. for 5 minutes. The proteins were separated on SDS-PAGE, and transferred to a PVDF-membrane for Western blot immuno analysis. Five sets of PVDF-membranes were prepared. The PVDF membranes were blocked/incubated overnight with 4% human sera/plasma, in phosphate buffered saline, from a patient with no H. pylori infection, i.e. with no serum antibodies against H. pylori . The membrane was then washed in phosphate buffered saline (PBS), 0.5% albumin, 0.05% Tween-20, followed by the addition of the antibody preparations. The sets of membranes were incubated with the following 5 antibody preparations; 1) pooled human sera from H. pylori infected patients, diluted 1:500. 2) Chicken antibodies (positive) 1 mg/ml diluted 1:100×, 3) Bovine I preparation of antibodies, 1 mg/ml diluted 1:100×. 4) Bovine II preparation of antibodies, 1 mg/ml diluted 1:100×. 5) Bovine III preparation of antibodies, 1 mg/ml diluted 1:100× (indicated in the figure). These antibodies were incubated with the membrane for 2 hours followed by extensive washings in phosphate buffered saline (PBS), 0.05% Tween-20, followed by the addition of secondary anti-human, anti-chicken, and anti-bovine antibodies labeled with HRP-peroxidase (from DAKO, Denmark), all diluted 1:2000×. Membranes were incubated for 1 hour, followed by extensive washings in phosphate buffered saline (PBS), 0.05% Tween-20. The membranes were developed with enhanced chemoluminescens (ECL) from Amersham. The results show, that the antigenic response against the adhesin is strongly enchanced in the bovine preparations. This finding is also supported by the inhibition data in FIG. 6. - Western blot analyses ofH. pylori proteins by the different antibody preparations are shown in FIG. 8. 2 clinical isolates (1-2) from Dr. Lars Engstrand, Department of Clinical Microbiology and Cancerepidemiology, University Hospital, Uppsala, Sweden and strain CCUG 17875 (3), from Culture Collection, University of Göteborg, Department of Clinical Bacteriology, Göteborg, Sweden, and strain 52 (4) from Prof. Torkel Wadström, Dept. Medical Microbiology, Lunds University, were prepared for SDS-PAGE electrophoresis. Bacterial pellets corresponding to 0.15 ml of bacteria (A600=OD 0.10) were dissolved in SDS sample buffer and heated to 100° C. for 5 minutes. The proteins were separated on SDS-PAGE, and transferred to PVDF-membranes for Western blot immuno analysis. The western blot analyses were as described above, i.e. the sets of membranes were incubated with the following 4 antibody preparations; 1) pooled human sera from H. pylori infected patients, diluted 1:500. 2) Chicken antibodies (positive) 1 mg/ml diluted 1:100×, 3) Bovine I preparation of antibodies, 1 mg/ml diluted 1:100×. 4) Bovine III preparation of antibodies, 1 mg/ml diluted 1:100× (indicated in the figure). These antibodies were incubated with the membrane for 2 hours followed by extensive washings in phosphate buffered saline (PBS), 0.05% Tween-20, followed by the addition of secondary anti-human, anti-chicken, and anti-bovine antibodies labeled with HRP-peroxidase (from DAKO, Denmark), all diluted 1:2000×. Membranes were incubated for 1 hour, followed by extensive washings in phosphate buffered saline (PBS), 0.05% Tween-20. The membranes were developed with enhanced chemoluminescens (ECL) from Amersham. The results show, that the chicken antibodies and the bovine preparations reacts nearly identically against all four strains, indicating conserved properties in strains of different geographical origin.
- Although the invention has been described with regard to its preferred embodiments, which constitute the best mode presently known to the inventors, it should be understood that various changes and modifications as would be obvious to one having the ordinary skill in this art may be made without departing from the scope of the invention which is set forth in the claims appended hereto.
- 1. J. R. Warren,Lancet, i, 1273, 1983, B. Marshall, Lancet, i, 1273, 1983.
- 2. A. Dubois,
Emerging Infectious Diseases 1, 79 (1995). - 3. M. J. Blaser,Sci. Amer. 2, 92 (1996).
- 4. 3. M. J. Blaser,Trends Microbiol. 7, 255 (1993), D. E. Kirschner and M. J. Blaser, J. Theor. Biol. 176, 281 (1995).
- 5. P. Falk, T. Borén, and S. Normark,Meth. Enzymol. 236, 353 (1994).
- 6. D. G. Evans, D. J. Evans Jr., J. J. Moulds and D. Y. Graham,Infect. Immun. 56, 2896 (1988), S. Hirmo, M. Utt, M. Ringner and T. Wadström, FEMS Immunol. and Med. Microbiol. 10, 301 (1995), T. Saitoh, et al FEBS Lett. 282, 385 (1991).
- 7. T. Borén, P. Falk, K. A. Roth, G. Larson, and S. Normark,Science. 262, 1892 (1993), P. Falk, et al Proc. Natl. Acad. Sci. U.S.A. 90, 2035 (1993).
- 8.H.
pylori strain CCUG 17875 was obtained from CCUG, Göteborg, Sweden. Strain A5, a gastric ulcer isolate, came from Astra Arcus, Södertälje, Sweden. Strains P466 and MO19 were described previously (7).Strain 26695 came from Dr. K. A. Eaton, The Ohio State University, and its genome was recently sequenced by The Institute for Genomic Research (TIGR), Rockville, Md. (J.-F. Tomb, et al, abstract 3B: 059, IX International Workshop on Gastroduodenal Pathology and Helicobacter pylori, Copenhagen, Denmark, 1996). The panel of 45 H. pylori clinical isolates came from the University Hospital in Uppsala, Sweden. Bacteria were grown at 37(C in 10% CO2 and 5% O2 for 48 h. - 9. All blood group antigen glycoconjugates used, i.e. semi-synthetic glycoproteins constructed by the conjugation of purified fucosylated oligosaccharides to serum albumin (7, 25), were from IsoSep AB, Tullinge, Sweden. The RIA was performed according to ref. 26 with some modifications; The H-1, Leb, Lea, H-2, Lex, and Ley glycoconjugates were 125I-labeled by the Chloramine T method. 1 ml of bacteria (A600=OD 0.10) was incubated with 300 ng of 125I-labeled conjugate (i.e. an excess of receptors) for 30 min. in phosphate buffered saline (PBS), 0.5% albumin, 0.05% Tween-20 (BB-buffer). After centrifugation, 125I-activity in the bacterial pellet was measured by gamma scintillation counting.
- 10. A. Covacci, et al,Proc. Natl. Acad. Sci. U.S.A. 90, 5791 (1993), M. Marchetti, et al, Science 267, 1655 (1995).
- 11 S. Censini et al,Proc. Natl. Acad. Sci. U.S.A. 93, 14648, (1996).
- 12. Z. Xiang, et al,Infect. Immun. 63, 94 (1995).
- 13. A. G. Scatchard,Ann. N. Y. Acad. Sci. 51, 600 (1949).
- 14. O. Mol, and B. Oudega,FEMS. Microbiol. Reviews, 19, 25 (1996).
- 15. Confocal microscopy was performed on a Nikon/Multiprobe 2001 instrument (Molecular Dynamics, Sunnyvale, Calif.). Electron microscopy was performed on a
JEOL 100 CX instrument. - 16. J. Brunner,Trends in Cell Biol. 6, 154 (1996), J. D. Bleil and P. M. Wassarman, Proc. Natl. Acad. Sci. U.S.A. 87, 5563, (1990).
- 17. M. M. Exner, P. Doig, T. J. Trust, and R. E. W. Hancock,Infect. Immun. 63, 1567 (1995), P. Doig, M. M. Exner, R. E. W. Hancock and T. J. Trust, J. Bacteriol. 177, 5447 (1995).
- 18. The BabA N-terminal sequence analysis was used to make degenerate oligonucleotides, which were used in PCR to obtain an amplified fragment from the chromosome of the babA gene. A 59 bp fragment was identified and used as probe for the screening of a low-copy plasmide (pACYC184) library of Sau3A partially digested chromosomal DNA from
strain CCUG 17875. - 19. P. Hagblom, E. Segal, E. Billyard, and M. So,Nature, 315, 156 (1985), R. Haas and T. F. Meyer, Cell, 44, 107 (1986).
- 20. A.-B. Jonsson, D. Ilver, P. Falk, J. Pepose, and S. Normark,Mol. Microbiol, 13, 403 (1994), N. Strömberg, P. G. Nyholm, I. Pascher, and S. Normark, Proc. Natl. Acad. Sci USA 88, 9340 (1991).
- 21. A. Kimura, K. T. Mountzouros, D. A. Relman, S. Falkow, J. L. Cowell,Infect. Immun. 58, 7 (1990).
- 22. T. Borén, and P. Falk,Sci. Amer., Sci. & Med. 4 (1994), L. S. Tompkins and S. Falkow, Science 267, 1621 (1995).
- 23. R. B. Ren, et al,Cell 63, 353 (1990).
- 24. P. G. Falk, L. Bry, J. Holgersson, and J. I. Gordon,Proc. Natl. Acad. Sci. U.S.A. 92, 1515 (1995).
- 25. P. D. Rye,Nature Biotechnology. 2, 155 (1996).
- 26 P. Falk, T. Borén, D. Haslam, M. G. Caparon,Meth. Cell Biol. 45, 161 (1994)
- 27. Cell extracts were prepared in SDS sample buffer without mercapto ethanol and heated at 37° C. or 97° C. for 10 min. before separation on SDS-PAGE. Proteins were blotted onto a PVDF membrane. The membrane was incubated with 1 μg/ml biotinylated Leb glycoconjugate or biotinylated albumin (negative control) overnight, labelled as described in
ref 7. After washing in PBS/0.05% Tween-20, the biotinylated structures bound by the BabA band were probed by HRP-streptavidin and detected using ECL reagents (Amersham, Buckinghamshire, England). - 28. The bacterial suspension was incubated with Leb glycoconjugate, to which the Sulfo-SBED crosslinker (Pierce, Rockville, Ill.) had been conjugated by the N-hydroxysuccinimide ester (NHS), according to the manufacturers specifications. The aryl azide crosslinker group was activated by UV irradiation (360 nm). Bacteria were washed with PBS pH 7.6, 0.05% Tween-20 and protease inhibitors (EDTA and benzamidine) under reducing conditions with 50 mM dithiothreitol (DTT). Bacterial proteins were separated on SDS-PAGE, and the biotin tagged BabA protein was detected by immunodetection (PVDF membrane/HRP-streptavidin and ECL) (FIG. 3C).
- 29. Strains
CCUG 17875 and A5 were first processed by crosslinking and DTT treatment, as above (28), followed by solubilisation in SDS sample buffer. The biotin tagged BabA protein was then extracted with streptavidin coated magnetic beads (Advanced Magnetics Inc., Cambridge, Mass.). The beads were boiled in SDS sample buffer, and bound proteins were eluted and alkylated. The protein preparation was further fractionated by preparative SDS-PAGE (Prep-Cell 491, BioRad, Hercules, Calif.). Fractions with the biotin tagged protein, i.e. the BabA fractions, were identified by immunodetection using streptavidin/ECL. The pooled BabA preparation was then separated on SDS-PAGE and transferred to PVDF membrane. The BabA band was excised and the BabA protein was N-terminally sequenced using a Procise™ 494 instrument (Applied Biosystems, Foster City, Calif.). -
1 9 1 3340 DNA Helicobacter pylori 1 tttcagtcaa gcccaaagct atgcgcaaaa cgcttatgct aaagagaatt tacaagcaca 60 gccgtccaag tatcaaaaca gcgtgcctga aatcaatatt gatgaagaag aaatcccctt 120 taagggttaa aattaaggag acattatgga aagaaaacgc tattcaaaac gctattgcaa 180 atacactgaa gctaaaatca gctttattga ctataaagat ttggacatgc tcaagcacac 240 gctatcagag cgctataaaa tcatgccaag gaggttgaca ggcaatagca aaaagtggca 300 agagagggtg gaagttagcg atcaaaagag cccgccacat ggctttaatc ccctacattg 360 tggataggaa aaaagtcgtg gatagccctt ttaaacagca ctgaattttt gattagggct 420 aatagggggc atgcctttta atcttgttta atcttggctc tatttttgtt aaacatcggt 480 tataaaagcg ttaaaagcac ttttaaaatc caattaaaag cgttcaaaag taacgcaaaa 540 aatcaaaaaa atgacaaaat ttttaagaaa atgacaaaaa aaaaaaaaac gctttatgct 600 ataatattcc aaatacattc taatgcaaat gcattctaat gcaaatgtat aatgaatgta 660 tgaaatccct aatattcaat ccaatttaat ccaaaaagga gaaaaaacac atcctttcat 720 taactttagg ctcgctttta gtttccactt tgagcgctga agacgacggc ttttacacaa 780 gcgtaggcta tcaaatcggt gaagccgctc aaatggtaac aaacaccaaa ggcatccaag 840 atctttcaga caactatgaa aacttgagca aacttttgac ccgatacagc accctaaaca 900 cccttatcaa attgtccgct gatccgagcg cgattaacgc ggcacgtgaa aatctgggcg 960 cgagcgcgaa gaacttgatc ggcgatacca aaaattcccc cgcctatcaa gccgtgcttt 1020 tggcgatcaa tgcggcggta gggttttgga atgtcttagg ctatgctacg caatgcgggg 1080 gtaacgctaa tggtcaagaa agcacctctt caaccaccat cttcaacaac gagccagggt 1140 atcgatccac ttccatcact tgcagtttga acaggtataa gcctggatac tacggcccta 1200 tgagcattga aaatttcaaa aagcttaacg aagcctatca aatcctccaa acggctttaa 1260 ataaaggctt acccgcgctc aaagaaaaca acggaacggt cagtgtaacc tacacctaca 1320 catgctcagg ggaagggaat gataactgct cgaaaaaagc cacaggtgta agtgaccaaa 1380 atggcggaac caaaactaaa acccaaacca tagacggcaa aaccgtaacc accacgatca 1440 gttcaaaagt cgttgatagt caggcaaaag gtaatacaac aagggtgtcc tacaccgaaa 1500 tcactaacaa attagacggt gtgcctgata gcgctcaagc gctcttggcg caagcgagca 1560 cgctcatcaa caccatcaac acggcatgcc cgtattttag tgtaactaat aaaagtggtg 1620 gtccacagat ggaaccgact agagggaagt tgtgcggttt tacagaagaa atcagcgcga 1680 tccaaaagat gatcacagac gcgcaagagc tggtcaatca aacgagcgtc attaacgagc 1740 atgaacaatc aaccccggta ggcggtaata atggcaagcc tttcaaccct ttcacggacg 1800 caagcttcgc tcaaggcatg ctcgctaacg ctagtgcgca agccaaaatg ctcaatctag 1860 cccatcaagt ggggcaaacc attaaccctg acaatcttac cgggactttt aaaaattttg 1920 ttacaggctt tttagccaca tgcaacaaca aatcaacagc tggcactagt ggcacacaag 1980 gttcacctcc tggcacagta accactcaaa ctttcgcttc cggttgcgcc tatgtggagc 2040 aaaccataac gaatctaaac aacagcatcg ctcattttgg cactcaagag cagcagatac 2100 agcaagctga aaacatcgct gacactctag tgaatttcaa atctagatac agcgaattag 2160 ggaatactta taacagcatc actactgcgc tctccaaagt ccctaacgcg caaagcttgc 2220 aaaacgtggt gggaaaaaag aataacccct atagcccgca aggcatagaa accaattact 2280 acttgaatca aaactcttac aaccaaatcc aaaccatcaa ccaagaatta gggcgtaacc 2340 cctttaggaa agtgggcatc gtcagttctc aaaccaacaa tggtgccatg aatgggatcg 2400 gtatccaggt gggctacaag caattctttg ggcaaaaaag gaaatggggt gcaagatact 2460 acggcttttt tgattacaac catgcgttca ttaaatccag cttcttcaac tcggcttctg 2520 acgtgtggac ttatggtttt ggagcggacg ctctttataa cttcatcaac gataaagcca 2580 ccaatttctt aggcaaaaac aacaagcttt ctgtggggct ttttggcggg attgcgttag 2640 cgggcacttc atggcttaat tctgaatacg tgaatttagc caccatgaat aacgtctata 2700 acgctaaaat gaacgtggcg aacttccaat tcttattcaa catgggagtg aggatgaatt 2760 tagccagatc caagaaaaaa ggcagcgatc atgcggctca gcatggcatt gagttagggc 2820 ttaaaatccc caccattaac acgaactact attcctttat gggggctgaa ctcaaatacc 2880 gcaggctcta tagcgtgtat ttgaattatg tgttcgctta ctaaaaacta aaaatccttt 2940 gtggaactcc ctttttaagg ggtttctttt aaagccttta tttttttttg gaggggttta 3000 atttttttga aacctttgtt tttgaattct ctttttaatg ggtttctttt ttgaactctt 3060 tgttttgaac tccttttttt gaactccctt ttttaaaccc tttctttttt aaaattctct 3120 tttttggggg gtttgatgaa aaatcctttt ttagcgtttt ggtattggtt agtggaaaac 3180 ttgatactaa tttaagcgat agtttttaaa aagtgcttct ttaatatagg gggtttaagt 3240 tggtgattaa aaggggggaa tggtttcaaa gcgcttccta tccctttaag aaaataaaat 3300 aaaactttaa taaaatgagt tttacaacaa aatgagatcc 3340 2 2781 DNA Helicobacter pylori 2 catttgatcg cattggattt caaagaaggg cgttttgtga aaggctttgg tcaagcttat 60 gatattttag gcgacaaaat cgcttatgtt gggggtaaag gcaacccaca caatttcgct 120 cacaagaaat aaactttctc acccataagg ggcaaacgcc cccaaaagag tgctttttaa 180 agaggttaag gcaaaatcaa gctctttagt atttaatctt aaaaaatact aaaagccttt 240 ttatgggcta acaccacaca aaaagcgtca aaatcaaaaa aatgacaaaa ttttccccaa 300 atgacaaaaa aaaaaaaaaa cgattttatg ctatattaac gaaatcttgt gataagatct 360 tattctttta aaagatttac ctaaccattt taatttcaag gagaaaacat gaaaaaaaac 420 ccttttactc tctctctctc tctctcgttt ttgctccacg ctgaagacga cggcttttac 480 acaagcgtag gctatcaaat cggtgaagcc gctcaaatgg taaccaacac caaaggcatc 540 caacagcttt cagacaatta tgaaaagctg aacaatcttt tgaataatta cagcacccta 600 aacaccctta tcaaattatc cgctgatccg agtgcgatta acgacgcaag ggataatcta 660 ggctcaagtg ctaagaattt gcttgatgtt aaaaccaact ccccggccta tcaagccgtg 720 cttttagcgt tgaatgcggc ggtggggttg tggcaagtta caagctacgc ttttactgct 780 tgtggtcctg gcagtaacga gagcgcaaat ggaggtatcc aaacttttaa taatgtgcca 840 ggacaaaaga cgacaaccat cacttgcaat tcgtattatc aaccaggaca tggtgggcct 900 atatccactg caaactatgc aaaaatcaat caagcctatc aaatcattca aaaggctttg 960 acagccaatg aagctaatgg agatggggtc cccgttttaa gcgacaccac tacaaaactt 1020 gatttcacta ttcaaggaga caaaagaacg ggtggccgac caaatacacc taaaaagttc 1080 ccatggagtg atgggaaata tattcacacc caatggattg acacaacacc acaatcaaca 1140 gaaacaaaga tcaacacaga aaataacgct caagagcttt taaaacaagc gagcatcatt 1200 atcactaccc taaatgaggc atgcccaaac ttccaaaatg gtggtagcgg ttattggcaa 1260 gggataagcg gcaatgggac aatgtgtggg atgtttaaga atgaaatcag cgctatccaa 1320 ggcatgatcg ctaacgcgca agaagctgtc gcgcaaagta aaatcgttag tgaaaatgcg 1380 caaaatcaaa acaacttgga tactggaaaa ccattcaacc ctttcacgga cgctagcttc 1440 gctcaaagca tgctcaaaaa cgctcaagcc caagcagaga ttttaaacca agccgaacaa 1500 gtggtgaaaa actttgaaaa aatccctaaa aattttgtat cagactcttt aggggtgtgt 1560 tatgaagagc aagggggtga gcgtaggggc accaatccag gtcaggttac ttctaacact 1620 ttcgcttccg gttgcgccta tgtggagcaa accataacga atctaaacaa cagcatcgct 1680 cattttggca ctcaagagca gcagatacag caagctgaaa acatcgctga cactctagtg 1740 aatttcaaat ctagatacag cgaattaggg aatacttata acagcatcac tactgcgctc 1800 tccaaagtcc ctaacgcgca aagcttgcaa aacgtggtgg gaaaaaagaa taacccctat 1860 agcccgcaag gcatagaaac caattactac ttgaatcaaa actcttacaa ccaaatccaa 1920 accatcaacc aagaattagg gcgtaacccc tttaggaaag tgggcatcgt cagttctcaa 1980 accaacaatg gtgccatgaa tgggatcggt atccaggtgg gctacaagca attctttggg 2040 caaaaaagga aatggggtgc aagatactac ggcttttttg attacaacca tgcgttcatt 2100 aaatccagct tcttcaactc ggcttctgac gtgtggactt atggttttgg agcggacgct 2160 ctttataact tcatcaacga taaagccacc aatttcttag gcaaaaacaa caagctttct 2220 gtggggcttt ttggcgggat tgcgttagcg ggcacttcat ggcttaattc tgaatacgtg 2280 aatttagcca ccatgaataa cgtctataac gctaaaatga acgtggcgaa cttccaattc 2340 ttattcaaca tgggagtgag gatgaattta gccagatcca agaaaaaagg cagcgatcat 2400 gcggctcagc atggcattga gttagggctt aaaatcccca ccattaacac gaactactat 2460 tcctttatgg gggctgaact caaataccgc aggctctata gcgtgtattt gaattatgtg 2520 ttcgcttact agaaactaaa aatcctttgt ggaactccct ttttaagggg tttcttttaa 2580 agcctttatt tttttttgga ggggtttaat ttttttgaaa cctttgtttt tgaattctct 2640 ttttaatggg tttctttttt gaactctttg ttttgaactc ctttttttga actccctttt 2700 ttaaaccctt tcttttttaa aattctcttt tttggggggt ttgatgaaaa atcctttttt 2760 agcgttttgg tattggttag t 2781 3 744 PRT Helicobacter pylori PEPTIDE (24)..(64) N-terminal domain of the BabA adhesin 3 Ser Lys Lys Glu Lys Lys His Ile Leu Ser Leu Thr Leu Gly Ser Leu 1 5 10 15 Leu Val Ser Thr Leu Ser Ala Glu Asp Asp Gly Phe Tyr Thr Ser Val 20 25 30 Gly Tyr Gln Ile Gly Glu Ala Ala Gln Met Val Thr Asn Thr Lys Gly 35 40 45 Ile Gln Asp Leu Ser Asp Asn Tyr Glu Asn Leu Ser Lys Leu Leu Thr 50 55 60 Arg Tyr Ser Thr Leu Asn Thr Leu Ile Lys Leu Ser Ala Asp Pro Ser 65 70 75 80 Ala Ile Asn Ala Ala Arg Glu Asn Leu Gly Ala Ser Ala Lys Asn Leu 85 90 95 Ile Gly Asp Thr Lys Asn Ser Pro Ala Tyr Gln Ala Val Leu Leu Ala 100 105 110 Ile Asn Ala Ala Val Gly Phe Trp Asn Val Leu Gly Tyr Ala Thr Gln 115 120 125 Cys Gly Gly Asn Ala Asn Gly Gln Glu Ser Thr Ser Ser Thr Thr Ile 130 135 140 Phe Asn Asn Glu Pro Gly Tyr Arg Ser Thr Ser Ile Thr Cys Ser Leu 145 150 155 160 Asn Arg Tyr Lys Pro Gly Tyr Tyr Gly Pro Met Ser Ile Glu Asn Phe 165 170 175 Lys Lys Leu Asn Glu Ala Tyr Gln Ile Leu Gln Thr Ala Leu Asn Lys 180 185 190 Gly Leu Pro Ala Leu Lys Glu Asn Asn Gly Thr Val Ser Val Thr Tyr 195 200 205 Thr Tyr Thr Cys Ser Gly Glu Gly Asn Asp Asn Cys Ser Lys Lys Ala 210 215 220 Thr Gly Val Ser Asp Gln Asn Gly Gly Thr Lys Thr Lys Thr Gln Thr 225 230 235 240 Ile Asp Gly Lys Thr Val Thr Thr Thr Ile Ser Ser Lys Val Val Asp 245 250 255 Ser Gln Ala Lys Gly Asn Thr Thr Arg Val Ser Tyr Thr Glu Ile Thr 260 265 270 Asn Lys Leu Asp Gly Val Pro Asp Ser Ala Gln Ala Leu Leu Ala Gln 275 280 285 Ala Ser Thr Leu Ile Asn Thr Ile Asn Thr Ala Cys Pro Tyr Phe Ser 290 295 300 Val Thr Asn Lys Ser Gly Gly Pro Gln Met Glu Pro Thr Arg Gly Lys 305 310 315 320 Leu Cys Gly Phe Thr Glu Glu Ile Ser Ala Ile Gln Lys Met Ile Thr 325 330 335 Asp Ala Gln Glu Leu Val Asn Gln Thr Ser Val Ile Asn Glu His Glu 340 345 350 Gln Ser Thr Pro Val Gly Gly Asn Asn Gly Lys Pro Phe Asn Pro Phe 355 360 365 Thr Asp Ala Ser Phe Ala Gln Gly Met Leu Ala Asn Ala Ser Ala Gln 370 375 380 Ala Lys Met Leu Asn Leu Ala His Gln Val Gly Gln Thr Ile Asn Pro 385 390 395 400 Asp Asn Leu Thr Gly Thr Phe Lys Asn Phe Val Thr Gly Phe Leu Ala 405 410 415 Thr Cys Asn Asn Lys Ser Thr Ala Gly Thr Ser Gly Thr Gln Gly Ser 420 425 430 Pro Pro Gly Thr Val Thr Thr Gln Thr Phe Ala Ser Gly Cys Ala Tyr 435 440 445 Val Glu Gln Thr Ile Thr Asn Leu Asn Asn Ser Ile Ala His Phe Gly 450 455 460 Thr Gln Glu Gln Gln Ile Gln Gln Ala Glu Asn Ile Ala Asp Thr Leu 465 470 475 480 Val Asn Phe Lys Ser Arg Tyr Ser Glu Leu Gly Asn Thr Tyr Asn Ser 485 490 495 Ile Thr Thr Ala Leu Ser Lys Val Pro Asn Ala Gln Ser Leu Gln Asn 500 505 510 Val Val Gly Lys Lys Asn Asn Pro Tyr Ser Pro Gln Gly Ile Glu Thr 515 520 525 Asn Tyr Tyr Leu Asn Gln Asn Ser Tyr Asn Gln Ile Gln Thr Ile Asn 530 535 540 Gln Glu Leu Gly Arg Asn Pro Phe Arg Lys Val Gly Ile Val Ser Ser 545 550 555 560 Gln Thr Asn Asn Gly Ala Met Asn Gly Ile Gly Ile Gln Val Gly Tyr 565 570 575 Lys Gln Phe Phe Gly Gln Lys Arg Lys Trp Gly Ala Arg Tyr Tyr Gly 580 585 590 Phe Phe Asp Tyr Asn His Ala Phe Ile Lys Ser Ser Phe Phe Asn Ser 595 600 605 Ala Ser Asp Val Trp Thr Tyr Gly Phe Gly Ala Asp Ala Leu Tyr Asn 610 615 620 Phe Ile Asn Asp Lys Ala Thr Asn Phe Leu Gly Lys Asn Asn Lys Leu 625 630 635 640 Ser Val Gly Leu Phe Gly Gly Ile Ala Leu Ala Gly Thr Ser Trp Leu 645 650 655 Asn Ser Glu Tyr Val Asn Leu Ala Thr Met Asn Asn Val Tyr Asn Ala 660 665 670 Lys Met Asn Val Ala Asn Phe Gln Phe Leu Phe Asn Met Gly Val Arg 675 680 685 Met Asn Leu Ala Arg Ser Lys Lys Lys Gly Ser Asp His Ala Ala Gln 690 695 700 His Gly Ile Glu Leu Gly Leu Lys Ile Pro Thr Ile Asn Thr Asn Tyr 705 710 715 720 Tyr Ser Phe Met Gly Ala Glu Leu Lys Tyr Arg Arg Leu Tyr Ser Val 725 730 735 Tyr Leu Asn Tyr Val Phe Ala Tyr 740 4 707 PRT Helicobacter pylori PEPTIDE (46)..(59) Corresponding to the N-terminal domain of the BabA adhesin 4 Met Lys Lys Asn Pro Phe Thr Leu Ser Leu Ser Leu Ser Phe Leu Leu 1 5 10 15 His Ala Glu Asp Asp Gly Phe Tyr Thr Ser Val Gly Tyr Gln Ile Gly 20 25 30 Glu Ala Ala Gln Met Val Thr Asn Thr Lys Gly Ile Gln Gln Leu Ser 35 40 45 Asp Asn Tyr Glu Lys Leu Asn Asn Leu Leu Asn Asn Tyr Ser Thr Leu 50 55 60 Asn Thr Leu Ile Lys Leu Ser Ala Asp Pro Ser Ala Ile Asn Asp Ala 65 70 75 80 Arg Asp Asn Leu Gly Ser Ser Ala Lys Asn Leu Leu Asp Val Lys Thr 85 90 95 Asn Ser Pro Ala Tyr Gln Ala Val Leu Leu Ala Leu Asn Ala Ala Val 100 105 110 Gly Leu Trp Gln Val Thr Ser Tyr Ala Phe Thr Ala Cys Gly Pro Gly 115 120 125 Ser Asn Glu Ser Ala Asn Gly Gly Ile Gln Thr Phe Asn Asn Val Pro 130 135 140 Gly Gln Lys Thr Thr Thr Ile Thr Cys Asn Ser Tyr Tyr Gln Pro Gly 145 150 155 160 His Gly Gly Pro Ile Ser Thr Ala Asn Tyr Ala Lys Ile Asn Gln Ala 165 170 175 Tyr Gln Ile Ile Gln Lys Ala Leu Thr Ala Asn Glu Ala Asn Gly Asp 180 185 190 Gly Val Pro Val Leu Ser Asp Thr Thr Thr Lys Leu Asp Phe Thr Ile 195 200 205 Gln Gly Asp Lys Arg Thr Gly Gly Arg Pro Asn Thr Pro Lys Lys Phe 210 215 220 Pro Trp Ser Asp Gly Lys Tyr Ile His Thr Gln Trp Ile Asp Thr Thr 225 230 235 240 Pro Gln Ser Thr Glu Thr Lys Ile Asn Thr Glu Asn Asn Ala Gln Glu 245 250 255 Leu Leu Lys Gln Ala Ser Ile Ile Ile Thr Thr Leu Asn Glu Ala Cys 260 265 270 Pro Asn Phe Gln Asn Gly Gly Ser Gly Tyr Trp Gln Gly Ile Ser Gly 275 280 285 Asn Gly Thr Met Cys Gly Met Phe Lys Asn Glu Ile Ser Ala Ile Gln 290 295 300 Gly Met Ile Ala Asn Ala Gln Glu Ala Val Ala Gln Ser Lys Ile Val 305 310 315 320 Ser Glu Asn Ala Gln Asn Gln Asn Asn Leu Asp Thr Gly Lys Pro Phe 325 330 335 Asn Pro Phe Thr Asp Ala Ser Phe Ala Gln Ser Met Leu Lys Asn Ala 340 345 350 Gln Ala Gln Ala Glu Ile Leu Asn Gln Ala Glu Gln Val Val Lys Asn 355 360 365 Phe Glu Lys Ile Pro Lys Asn Phe Val Ser Asp Ser Leu Gly Val Cys 370 375 380 Tyr Glu Glu Gln Gly Gly Glu Arg Arg Gly Thr Asn Pro Gly Gln Val 385 390 395 400 Thr Ser Asn Thr Phe Ala Ser Gly Cys Ala Tyr Val Glu Gln Thr Ile 405 410 415 Thr Asn Leu Asn Asn Ser Ile Ala His Phe Gly Thr Gln Glu Gln Gln 420 425 430 Ile Gln Gln Ala Glu Asn Ile Ala Asp Thr Leu Val Asn Phe Lys Ser 435 440 445 Arg Tyr Ser Glu Leu Gly Asn Thr Tyr Asn Ser Ile Thr Thr Ala Leu 450 455 460 Ser Lys Val Pro Asn Ala Gln Ser Leu Gln Asn Val Val Gly Lys Lys 465 470 475 480 Asn Asn Pro Tyr Ser Pro Gln Gly Ile Glu Thr Asn Tyr Tyr Leu Asn 485 490 495 Gln Asn Ser Tyr Asn Gln Ile Gln Thr Ile Asn Gln Glu Leu Gly Arg 500 505 510 Asn Pro Phe Arg Lys Val Gly Ile Val Ser Ser Gln Thr Asn Asn Gly 515 520 525 Ala Met Asn Gly Ile Gly Ile Gln Val Gly Tyr Lys Gln Phe Phe Gly 530 535 540 Gln Lys Arg Lys Trp Gly Ala Arg Tyr Tyr Gly Phe Phe Asp Tyr Asn 545 550 555 560 His Ala Phe Ile Lys Ser Ser Phe Phe Asn Ser Ala Ser Asp Val Trp 565 570 575 Thr Tyr Gly Phe Gly Ala Asp Ala Leu Tyr Asn Phe Ile Asn Asp Lys 580 585 590 Ala Thr Asn Phe Leu Gly Lys Asn Asn Lys Leu Ser Val Gly Leu Phe 595 600 605 Gly Gly Ile Ala Leu Ala Gly Thr Ser Trp Leu Asn Ser Glu Tyr Val 610 615 620 Asn Leu Ala Thr Met Asn Asn Val Tyr Asn Ala Lys Met Asn Val Ala 625 630 635 640 Asn Phe Gln Phe Leu Phe Asn Met Gly Val Arg Met Asn Leu Ala Arg 645 650 655 Ser Lys Lys Lys Gly Ser Asp His Ala Ala Gln His Gly Ile Glu Leu 660 665 670 Gly Leu Lys Ile Pro Thr Ile Asn Thr Asn Tyr Tyr Ser Phe Met Gly 675 680 685 Ala Glu Leu Lys Tyr Arg Arg Leu Tyr Ser Val Tyr Leu Asn Tyr Val 690 695 700 Phe Ala Tyr 705 5 20 PRT Helicobacter pylori 5 Glu Asp Asp Gly Phe Tyr Thr Ser Val Gly Tyr Gln Ile Gly Glu Ala 1 5 10 15 Ala Gln Met Val 20 6 60 DNA Helicobacter pylori 6 gaagacgacg gcttttacac aagcgtaggc tatcaaatcg gtgaagccgc tcaaatggta 60 7 41 PRT Helicobacter pylori 7 Glu Asp Asp Gly Phe Tyr Thr Ser Val Gly Tyr Gln Ile Gly Glu Ala 1 5 10 15 Ala Gln Met Val Thr Asn Thr Lys Gly Ile Gln Asp Leu Ser Asp Asn 20 25 30 Tyr Glu Asn Leu Ser Lys Leu Leu Thr 35 40 8 20 PRT Helicobacter pylori 8 Glu Asp Asp Gly Phe Tyr Thr Ser Val Gly Tyr Gln Ile Gly Glu Ala 1 5 10 15 Ala Gln Met Val 20 9 41 PRT Helicobacter pylori 9 Glu Asp Asp Gly Phe Tyr Thr Ser Val Gly Tyr Gln Ile Gly Glu Ala 1 5 10 15 Ala Gln Met Val Thr Asn Thr Lys Gly Ile Gln Gln Leu Ser Asp Asn 20 25 30 Tyr Glu Lys Leu Asn Asn Leu Leu Asn 35 40
Claims (26)
1. A vaccine comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:6.
2. A test kit comprising a monospecific antisera produced using an isolated and purified bacterial blood group antigen binding adhesin protein (BabA) from Helicobacter pylori species, wherein said protein binds specifically to fucosylated Lewisb type I and H-1 blood group antigen-glycoconjugates and,
wherein said protein contains less than 20% bacterial protein impurities, has a molecular weight in the interval of 73 to 75 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and is not a HopA, HopB, HopC, HopD, or HopE protein.
3. An immunoglobulin composition, wherein said composition exhibits specific activity to a Lewisb binding adhesin protein or fractions thereof, expressed by Helicobacter pylori.
4. The immunoglobulin composition according to claim 3 , wherein said adhesin in its unfractionated form has a molecular weight in the interval of about 70 to 77 kDa, preferably in the interval of 73 to 75 kDa and most preferably about 73500 kDa, as determined by SDS-PAGE.
5. The immunoglobulin composition according to any one of claims 3 or 4 wherein said adhesin or fractions thereof comprises the following amino acid sequence:
EDDGFYTSVGYQIGEAAQMV (SEQ ID NO:5)
or homologues thereof.
6. An antibody, which exhibits specific activity to a Lewisb binding adhesin protein or fractions thereof, expressed by Helicobacter pylori.
7. The antibody according to claim 6 , wherein said adhesin in its unfractionated form has a molecular weight in the interval of about 70 to 77 kDa, preferably in the interval of 73 to 75 kDa and most preferably about 73500 kDa, as determined by SDS-PAGE.
8. The antibody according to any one of claims 6 or 7, wherein said adhesin or fractions thereof comprises the following amino acid sequence:
EDDGFYTSVGYQIGEAAQMV (SEQ ID NO:5)
or homologues thereof.
9. The antibody according to claim 6 , wherein said antibody is a monoclonal antibody.
10. A method of manufacturing an immunoglobulin composition according to claim 3 , comprising the following steps:
immunizing an animal with a Lewisb binding adhesin protein or fractions thereof, expressed by Helicobacter pylori,
isolating the immunoglobulin fraction from an excretion of said host animal, and
purifying of the immunoglobulin preparation.
11. The method according to claim 10 , wherein said animal is a cow and the immunoglobulin fraction is isolated from the milk, preferably the colostrum thereof.
12. The method according to claim 10 , wherein said animal is a chicken and the immunoglobulin fraction is isolated from the egg yolk thereof.
13. A method of manufacturing an antibody according to claim 6 , wherein method comprises the following steps:
immunizing an animal with a Lewisb binding adhesin protein or fractions thereof, expressed by Helicobacter pylori,
fusing immunised, immunoglobulin producing cells with a neoplastic cell line,
selecting and growing cells expressing said antibody, and
purifying the antibodies.
14. The method of claim 13 , further comprising expressing said antibody by a culture of viable microorganisms in an expression system, where said microorganisms or organisms are generally recognised as safe (GRAS) and genetically modified to express said antibody.
15. The method according to claim 14 , wherein said microorganism is selected from the group consisting of bacteria of the species Lactobacillus, Staphylococcus and Enteriobacteriacea.
16. A pharmaceutical preparation for the treating and/or preventing Helicobacter pylori infection in humans comprising the immunoglobulin composition according to claim 3 .
17. A pharmaceutical product for the treating and/or preventing gastric ulcers comprising the immunoglobulin composition according to claim 3 .
18. A pharmaceutical product for the treating and/or preventing acid peptic disease comprising comprising the immunoglobulin composition according to claim 3 .
19. A pharmaceutical product for the treating and/or preventing Helicobacter pylori infection in humans comprising the antibody according to claim 6 .
20. A pharmaceutical product for the treating and/or preventing gastric ulcers comprising the antibody according to claim 6 .
21. A pharmaceutical product for the treating and/or preventing acid peptic disease comprising the antibody according to claim 6 .
22. A method for treating and/or preventing Helicobacter pylori infections in a human, comprising the step of orally administering an effective amount of an immunoglobulin composition according to claim 3 to said human.
23. A method for treating and/or preventing Helicobacter pylori infections in a human, comprising orally administering an effective amount of an antibody according to claim 6 to said human.
24. A method for treating and/or preventing Helicobacter pylori infections in a human, said method comprising orally administering an effective amount of a culture of viable microorganisms in an expression system, wherein said microorganism or organisms are generally recognised as safe (GRAS) and genetically modified to express an antibody according to any one of claims 8 to 9 .
25. An expression system, comprising a culture of viable microorganisms wherein said microorganism or organisms are generally recognised as safe (GRAS) and genetically modified to express an antibody according to any one of claims 8-9.
26. A method for treating and/or preventing Helicobacter pylori infections in humans, said method comprising orally administering an effective amount of a culture of viable microorganisms in an expression system, wherein said microorganisms or organisms are generally recognised as safe (GRAS) and genetically modified to express an adhesin protein according to claim 1.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/761,201 US7271251B2 (en) | 1996-06-10 | 2004-01-22 | Helicobacter pylori adhesin binding group antigen |
US11/762,720 US20080187541A1 (en) | 1996-06-10 | 2007-06-13 | Helicobacter pylori adhesin binding group antigen |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9602287A SE9602287D0 (en) | 1996-06-10 | 1996-06-10 | Novel protein and methods for its use |
SE9602287-6 | 1996-06-10 | ||
SE9701014-4 | 1997-03-19 | ||
SE9701014A SE9701014D0 (en) | 1997-03-19 | 1997-03-19 | Novel polynucleotides and methods for their use |
US09/202,178 US6709656B1 (en) | 1996-06-10 | 1997-06-10 | Helicobacter pylori adhesin binding group antigen |
US10/761,201 US7271251B2 (en) | 1996-06-10 | 2004-01-22 | Helicobacter pylori adhesin binding group antigen |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/SE1997/001009 Division WO1997047646A1 (en) | 1996-06-10 | 1997-06-10 | Helicobacter pylori adhesin binding group antigen |
US09/202,178 Division US6709656B1 (en) | 1996-06-10 | 1997-06-10 | Helicobacter pylori adhesin binding group antigen |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/762,720 Division US20080187541A1 (en) | 1996-06-10 | 2007-06-13 | Helicobacter pylori adhesin binding group antigen |
Publications (2)
Publication Number | Publication Date |
---|---|
US20040234529A1 true US20040234529A1 (en) | 2004-11-25 |
US7271251B2 US7271251B2 (en) | 2007-09-18 |
Family
ID=26662671
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/202,178 Expired - Fee Related US6709656B1 (en) | 1996-06-10 | 1997-06-10 | Helicobacter pylori adhesin binding group antigen |
US10/761,201 Expired - Fee Related US7271251B2 (en) | 1996-06-10 | 2004-01-22 | Helicobacter pylori adhesin binding group antigen |
US11/762,720 Abandoned US20080187541A1 (en) | 1996-06-10 | 2007-06-13 | Helicobacter pylori adhesin binding group antigen |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/202,178 Expired - Fee Related US6709656B1 (en) | 1996-06-10 | 1997-06-10 | Helicobacter pylori adhesin binding group antigen |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/762,720 Abandoned US20080187541A1 (en) | 1996-06-10 | 2007-06-13 | Helicobacter pylori adhesin binding group antigen |
Country Status (10)
Country | Link |
---|---|
US (3) | US6709656B1 (en) |
EP (1) | EP0909272B1 (en) |
JP (1) | JP4112011B2 (en) |
AT (1) | ATE353337T1 (en) |
AU (1) | AU726429B2 (en) |
CA (1) | CA2257826C (en) |
DE (1) | DE69737323T2 (en) |
ES (1) | ES2281914T3 (en) |
NZ (1) | NZ333250A (en) |
WO (1) | WO1997047646A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008105740A1 (en) * | 2007-03-01 | 2008-09-04 | Helicure Ab | A new immunoglobulin against helicobacter pylori |
CN113846080A (en) * | 2021-09-06 | 2021-12-28 | 尤丽康(江苏)生物医药有限公司 | Helicobacter pylori composite antigen, helicobacter pylori antibody, preparation method and application |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2281914T3 (en) * | 1996-06-10 | 2007-10-01 | Thomas Boren | ANTIGEN OF THE ADHESINE GROUP OF HELICOBACTER PYLORI. |
US6410719B1 (en) * | 1996-06-10 | 2002-06-25 | Thomas Boren | Blood group antigen binding protein and corresponding agents |
AU4718999A (en) * | 1998-06-26 | 2000-01-17 | American Cyanamid Company | Novel antigens of (helicobacter pylori) |
SE9904581D0 (en) * | 1999-12-15 | 1999-12-15 | A & Science Invest Ab | A novel helicobacter pylori-binding substance and its use |
WO2002066502A1 (en) * | 2001-02-21 | 2002-08-29 | Boren Thomas | Helicobacter pylori sialic acid binding adhesin, saba and saba - gene |
SE0103695D0 (en) | 2001-11-07 | 2001-11-07 | Thomas Boren | A novel non-antibiotic strategy against OGIP infections based on a cereal product |
US20040126811A1 (en) * | 2002-02-21 | 2004-07-01 | Thomas Boren | Helicobacter pylori sialic acid binding adhesin, saba and saba-gene |
US7326770B2 (en) * | 2004-01-22 | 2008-02-05 | Neose Technologies, Inc. | H. pylori fucosyltransferases |
GB2427194A (en) * | 2005-06-16 | 2006-12-20 | Domantis Ltd | Single domain Helicobacter pylori adhesin antibodies |
US9616114B1 (en) | 2014-09-18 | 2017-04-11 | David Gordon Bermudes | Modified bacteria having improved pharmacokinetics and tumor colonization enhancing antitumor activity |
US11180535B1 (en) | 2016-12-07 | 2021-11-23 | David Gordon Bermudes | Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444879A (en) * | 1981-01-29 | 1984-04-24 | Science Research Center, Inc. | Immunoassay with article having support film and immunological counterpart of analyte |
US5258177A (en) * | 1991-12-10 | 1993-11-02 | Alpha Therapeutic Corporation | IgA preparation and process of making the same |
US5538729A (en) * | 1992-04-13 | 1996-07-23 | Oravax, Inc. | Oral treatment of helicobacter infection |
US5625124A (en) * | 1994-07-11 | 1997-04-29 | Washington University | Animal model for helicobacter pylori infection |
US5837502A (en) * | 1993-06-30 | 1998-11-17 | Reckitt & Colman Products Limited | Helicobacter pylori haemagglutinin protease protein, nucleic acid encoding therefor and antibodies specific thereto |
US5846751A (en) * | 1990-12-04 | 1998-12-08 | Quidel Corporation | Test kits and methods for detecting H. pylori |
US5883079A (en) * | 1992-07-31 | 1999-03-16 | Neose Technologies, Inc. | Method for inhibiting H. pylori infection in mammalian tissue |
US5897475A (en) * | 1994-10-05 | 1999-04-27 | Antex Biologics, Inc. | Vaccines comprising enhanced antigenic helicobacter spp. |
US6051416A (en) * | 1994-10-05 | 2000-04-18 | Antex Biologics Inc. | Methods for producing enhanced antigenic Helicobacter sp. |
US6410719B1 (en) * | 1996-06-10 | 2002-06-25 | Thomas Boren | Blood group antigen binding protein and corresponding agents |
US6709656B1 (en) * | 1996-06-10 | 2004-03-23 | Thomas Boren | Helicobacter pylori adhesin binding group antigen |
Family Cites Families (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK219084D0 (en) * | 1984-05-02 | 1984-05-02 | Frederik Carl Peter Lindberg | ANTIGEN |
DE69133120T2 (en) | 1990-07-17 | 2003-05-15 | Univ Oklahoma Norman Board Of | GMP-140 ligand |
US5258178A (en) * | 1990-07-30 | 1993-11-02 | Abbott Laboratories | Method and product for the treatment of gastric disease |
US5567594A (en) * | 1991-04-26 | 1996-10-22 | Enteron, L.P. | Methods and compositions for the detection and treatment of diseases associated with antigens of microorganisms |
US5262156A (en) * | 1991-08-12 | 1993-11-16 | Hycor Biomedical, Inc. | Antigenic compositions and their use for the detection of Helicobacter pylori |
US6290962B1 (en) * | 1992-11-03 | 2001-09-18 | Oravax, Inc. | Urease-based vaccine and treatment for helicobacter infection |
US6258359B1 (en) * | 1993-05-19 | 2001-07-10 | Institut Pasteur | Immunogenic compositions against helicobacter infection, polypeptides for use in the compositions, and nucleic acid sequences encoding said polypeptides |
US5679769A (en) * | 1994-03-15 | 1997-10-21 | Sloan-Kettering Institute For Cancer Research | Synthesis of asparagine-linked glycopeptides on a polymeric solid support |
US5708163A (en) * | 1994-03-15 | 1998-01-13 | Sloan-Kettering Institute Of Cancer Research | Synthesis of the breast tumor-associated antigen defined by monoclonalantibody MBRL and uses thereof |
FR2724936A1 (en) * | 1994-09-22 | 1996-03-29 | Pasteur Merieux Serums Vacc | Protein isolated from Helicobacter pylori membrane |
WO1996033220A1 (en) * | 1995-04-21 | 1996-10-24 | Csl Limited | Protective helicobacter antigens |
DE19521314A1 (en) * | 1995-06-12 | 1996-12-19 | Max Planck Gesellschaft | Adherence gene from Helicobacter pylori and polypeptide encoded thereby |
DE19521312A1 (en) * | 1995-06-12 | 1996-12-19 | Max Planck Gesellschaft | Procedure for the identification of secretory genes from Helicobacter pylori |
FR2739623B1 (en) * | 1995-10-04 | 1997-12-05 | Pasteur Merieux Serums Vacc | NEW MEMBRANE PROTEIN P76 FROM HELICOBACTER PYLORI |
CA2182046A1 (en) * | 1996-07-25 | 1998-01-26 | Clifford A. Lingwood | Haemophilus adhesin protein |
JP3430853B2 (en) * | 1997-04-11 | 2003-07-28 | 株式会社ゲン・コーポレーション | Preventive and therapeutic agents for gastritis, gastric ulcer and duodenal ulcer |
US20020151462A1 (en) * | 1998-02-19 | 2002-10-17 | Ling Lissolo | Helicobacter pylori membrane proteins |
CA2335487A1 (en) * | 1998-06-19 | 1999-12-23 | Merieux Oravax | Lt and ct in parenteral immunization methods against helicobacter infection |
US6238894B1 (en) * | 1998-11-04 | 2001-05-29 | Diane Taylor | α1,2 fucosyltransferase |
US20020086032A1 (en) * | 1999-02-02 | 2002-07-04 | Mahan Michael J. | Producing antibodies with attenuated bacteria with altered DNA adenine methylase activity |
EP1278768B1 (en) * | 2000-04-27 | 2006-11-15 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Method for identifying helicobacter antigens |
JP2002029999A (en) * | 2000-07-14 | 2002-01-29 | Gen Corp:Kk | Prophylactic and therapeutic agent for digestive ulcer |
SE0103695D0 (en) * | 2001-11-07 | 2001-11-07 | Thomas Boren | A novel non-antibiotic strategy against OGIP infections based on a cereal product |
US20050009037A1 (en) * | 2002-08-16 | 2005-01-13 | Yung-Fu Chang | Helicobacter bizzozeronii outer membrane protein encoding gene and its use in diagnostic and treatment methods |
BRPI0516681A (en) * | 2004-11-25 | 2008-09-16 | Unilever Nv | antibody delivery system to the gastrointestinal tract, expression vector, transformed microorganisms, antibody delivery method, heavy chain immunoglobulins and their use, food product and its method of manufacture and delivery tool |
US8025880B2 (en) * | 2007-03-01 | 2011-09-27 | Helicure Ab | Immunoglobulin against Helicobacter pylori |
-
1997
- 1997-06-10 ES ES97927563T patent/ES2281914T3/en not_active Expired - Lifetime
- 1997-06-10 WO PCT/SE1997/001009 patent/WO1997047646A1/en active IP Right Grant
- 1997-06-10 US US09/202,178 patent/US6709656B1/en not_active Expired - Fee Related
- 1997-06-10 JP JP50151598A patent/JP4112011B2/en not_active Expired - Fee Related
- 1997-06-10 DE DE69737323T patent/DE69737323T2/en not_active Expired - Lifetime
- 1997-06-10 AT AT97927563T patent/ATE353337T1/en active
- 1997-06-10 EP EP97927563A patent/EP0909272B1/en not_active Expired - Lifetime
- 1997-06-10 NZ NZ333250A patent/NZ333250A/en unknown
- 1997-06-10 CA CA2257826A patent/CA2257826C/en not_active Expired - Fee Related
- 1997-06-10 AU AU31999/97A patent/AU726429B2/en not_active Ceased
-
2004
- 2004-01-22 US US10/761,201 patent/US7271251B2/en not_active Expired - Fee Related
-
2007
- 2007-06-13 US US11/762,720 patent/US20080187541A1/en not_active Abandoned
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444879A (en) * | 1981-01-29 | 1984-04-24 | Science Research Center, Inc. | Immunoassay with article having support film and immunological counterpart of analyte |
US5846751A (en) * | 1990-12-04 | 1998-12-08 | Quidel Corporation | Test kits and methods for detecting H. pylori |
US5258177A (en) * | 1991-12-10 | 1993-11-02 | Alpha Therapeutic Corporation | IgA preparation and process of making the same |
US5538729A (en) * | 1992-04-13 | 1996-07-23 | Oravax, Inc. | Oral treatment of helicobacter infection |
US5883079A (en) * | 1992-07-31 | 1999-03-16 | Neose Technologies, Inc. | Method for inhibiting H. pylori infection in mammalian tissue |
US5837502A (en) * | 1993-06-30 | 1998-11-17 | Reckitt & Colman Products Limited | Helicobacter pylori haemagglutinin protease protein, nucleic acid encoding therefor and antibodies specific thereto |
US5625124A (en) * | 1994-07-11 | 1997-04-29 | Washington University | Animal model for helicobacter pylori infection |
US5897475A (en) * | 1994-10-05 | 1999-04-27 | Antex Biologics, Inc. | Vaccines comprising enhanced antigenic helicobacter spp. |
US6051416A (en) * | 1994-10-05 | 2000-04-18 | Antex Biologics Inc. | Methods for producing enhanced antigenic Helicobacter sp. |
US6410719B1 (en) * | 1996-06-10 | 2002-06-25 | Thomas Boren | Blood group antigen binding protein and corresponding agents |
US6709656B1 (en) * | 1996-06-10 | 2004-03-23 | Thomas Boren | Helicobacter pylori adhesin binding group antigen |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008105740A1 (en) * | 2007-03-01 | 2008-09-04 | Helicure Ab | A new immunoglobulin against helicobacter pylori |
US20080213224A1 (en) * | 2007-03-01 | 2008-09-04 | Thomas Boren | Immunoglobulin against helicobacter pylori |
JP2010519901A (en) * | 2007-03-01 | 2010-06-10 | ヘリキュア アクチボラゲット | Novel immunoglobulins against H. pylori |
US8025880B2 (en) | 2007-03-01 | 2011-09-27 | Helicure Ab | Immunoglobulin against Helicobacter pylori |
CN113846080A (en) * | 2021-09-06 | 2021-12-28 | 尤丽康(江苏)生物医药有限公司 | Helicobacter pylori composite antigen, helicobacter pylori antibody, preparation method and application |
Also Published As
Publication number | Publication date |
---|---|
AU3199997A (en) | 1998-01-07 |
US20080187541A1 (en) | 2008-08-07 |
NZ333250A (en) | 2000-05-26 |
DE69737323D1 (en) | 2007-03-22 |
CA2257826C (en) | 2011-11-22 |
JP4112011B2 (en) | 2008-07-02 |
JP2001503606A (en) | 2001-03-21 |
ES2281914T3 (en) | 2007-10-01 |
CA2257826A1 (en) | 1997-12-18 |
US6709656B1 (en) | 2004-03-23 |
WO1997047646A1 (en) | 1997-12-18 |
EP0909272A1 (en) | 1999-04-21 |
AU726429B2 (en) | 2000-11-09 |
ATE353337T1 (en) | 2007-02-15 |
US7271251B2 (en) | 2007-09-18 |
EP0909272B1 (en) | 2007-02-07 |
DE69737323T2 (en) | 2007-11-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080187541A1 (en) | Helicobacter pylori adhesin binding group antigen | |
Sperandio et al. | The OmpU outer membrane protein, a potential adherence factor of Vibrio cholerae | |
Amani et al. | Immunogenic properties of chimeric protein from espA, eae and tir genes of Escherichia coli O157: H7 | |
JP5349448B2 (en) | P. gingivalis antigen composition | |
CA2040544C (en) | Actinobacillus pleuropneumoniae subunit vaccine | |
JP2004159660A (en) | Deletion mutant as vaccine for cholera | |
JP2008249712A (en) | Histidine-tagged intimin and method of using intimin to stimulate immune response and as antigen carrier with targeting capability | |
US5888810A (en) | Campylobacteri jejuni flagellin-escherichia coli LT-B fusion protein | |
JP2000125889A (en) | Protein from actinobacillus pleuropneumoniae | |
JPH11504633A (en) | Multimeric recombinant urease vaccine | |
US7608266B2 (en) | Yersinia species compositions | |
JP3169608B2 (en) | Preparation and use of formalin-killed colony-forming factor antigen (CFA) -expressing E. coli for inoculation against enteric infections / diarrhea caused by enterotoxin-producing E. coli in humans | |
US5798260A (en) | Escherichia coli O157:H7 epithelial adhesin | |
US6036953A (en) | Heterologous antigens in live cell V. cholerae strains | |
IE60324B1 (en) | Vaccine against e. coli septicaemia in poultry | |
US20020028210A1 (en) | Vaccine composition comprising helicobacter pylori flagellin polypeptide | |
US6410719B1 (en) | Blood group antigen binding protein and corresponding agents | |
JP2001523954A (en) | 76 kDa, 32 kDa, and 50 kDa Helicobacter polypeptides and corresponding polynucleotide molecules | |
RU2140981C1 (en) | Avirulent strain vibrio cholerae of non 01-serogroup (variants), method of strain preparing (variants), vaccine | |
Schoolnik et al. | Uropathogenic Escherichia coli: molecular mechanisms of adherence | |
CN116782926A (en) | High dose shigella vaccine formulations | |
MXPA97009194A (en) | Antigens of helicobacter pylori and compositions of vac |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FPAY | Fee payment |
Year of fee payment: 4 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20150918 |